Entera Bio Ltd. (ENTX) Earnings Call Transcript & Summary

Good morning, and welcome to the Entera Bio Key Opinion Leader Webinar on the treatment landscape for osteoporosis and EB613 potential impact. [Operator Instructions]. Before we begin, please note that this presentation, including all verbal remarks contain forward-looking statements, the accuracy of which depends on future events outside the company's control, and therefore, might cause actual results to differ materially from those forward-looking statements. In the case of any questions or discrepancies, we defer to the company's public documents available from its website and filed with the SEC. I'd now like to turn the call over to Dr. John Bilezikian to take the presentation off. Please go ahead, Dr. Bilezikian.

Tara, thank you very much. It's a pleasure for me to join my colleagues in this presentation. My credentials are here. I'm a professional medicine at the Vagelos College of Physicians and Surgeons. I have spent my entire career at Columbia except for 2 years at the NIH. And my passion has been parathyroid hormone in all kinds of ways and how it relates to the diseases of parathyroid hormone as well as its relationship to osteoporosis. Next slide, please. So my introductory remarks will set the stage for big comments to follow. Let's start with a description of this very important disease. It is really one of the most important public health problems. And as you can see in the United States, we are dealing with a major issue with regard to the endpoint of this disorder, namely the osteoporotic fracture. There are over 2 million such fractures in the United States. And as you can see in the graph, it is projected to increase to over 3 million over the next 10 or 20 years. Those at risk are a major percentage of the women in this country, 54 million, 10 million already have lost to osteoporosis with another 40 million or so that are at risk. And so brain comment, one fracture is occurring every 16 seconds. So since I started, there have been about 4 fractures or so. So we have an issue here, not just for women, but also related to men who also are at risk for osteoporosis. Next slide, please. Next slide. Thank you. Going to the globe is pervasive, over 200 million women worldwide. And you can see the percentages of those as women age, but it isn't just a disorder of the elderly. It's a disorder of middle-aged women as well. 30% of women over the age of 50 are shown to have had one or more vertebral fractures. So this is not a national problem. It's an international problem. Next slide, please. This is an interesting cartoon that shows on the left, what happens as aging intervene in terms of our skeletal health. Healthy boneless is a depiction of a hip. And in the middle of this slide, you can see the deteriorated microstructure, and this leads to stress fractures and ultimately, the major femoral neck fracture, which is one of the major osteoporotic fractures that we are dealing with. The underlying mechanism of this progression of microarchitectural deterioration is shown on the right side of this slide, we are dealing with a disorder of bone metabolism. Bone metabolism depends upon a regular cycling, whereby old bone is replaced by new bone. And that process, we call be remodeling with the cells of those multinucleated giant cells called osteoclast, taking a little bite out of bone. And you can see these arrows are showing the flow of restoration such that old piece of bone is replaced by new bone, first, collagen and then it is mineralized. This process of bone remodeling is out of whack when we're dealing with the mechanism of bone loss in osteoporosis. We're dealing either with osteoclasts that are overactive with osteoblast to keep up. The osteoblasts are the begin forming cells or sometimes we have an issue where the osteoblast are primarily under active. And I think in many cases, we're dealing with overactive osteoclasts and underactive osteoblasts. So a disorder of bone remodeling, we think, is the basic pathophysiological process that leads to the clinical problem of osteoporosis. Next slide, please. This is a summary table of the drugs that we call antiresorptives. These drugs block the actions of the osteoclast. There are different mechanisms. They represent different classes. The [ bisphosphonate ], you can see there's estrogen, of course, there's denosumab raloxifene and calcitonin. These drugs are variably efficacious. The pluses indicate those fights for which there is good evidence for fracture efficacy. And obviously, we're looking for drugs that have, what we say, global efficacy with the pluses indicating that information with pluses across the board, we would be very much more interested in those drugs as an option for osteoporosis than drugs that have a more limited efficacy profile. Next slide, please. I mentioned the problem of abnormal bone remodeling. The table I just showed you is based upon an effect at that early stage of the bone remodeling process, namely bone resorption. And what these drugs do, again, variably is to inhibit or in some case, kill those multi-nucleated cells. And by impairing the activity of the osteoclast, there is a partial, a restoration of bone balance and thus, one of the reasons why these drugs seem to be effective is that they help to restate or reset that remodeling system and allow for bone gain. Next slide, please. The antiresorptives are effective. They have been with us for -- in this country for over 27 years. And as you can see by this slide, they do help to prevent that process of further microstructural deterioration. As you can see, the top panel, the middle panel, the bottom panel, that is the progression of the microstructural issue. And these antiresorptives do help to prevent that process. And as now on the left side, they do stabilize often increase bone density. They don't improve, but they will maintain trabecular microstructure and they do, in some cases, increase the mineralization density of the bone matrix. Next slide. Let me, again, focus on the microstructure of bone because that is the crux of the problem. On the left, you see this beautiful honey coming, microstructural depiction of normal trabecular bone. And on the right, again, you can see this broken-down bone. There is disconnectivity. Those arrows indicate the trabecular specials that have broken off. And the real challenge in this disease is to restore that microstructural defects. Next slide. Again, showing this in cartoon form. We'd like to reverse the process. And the idea is to use therapeutics that have potential to restore microstructure. The red arrows indicate the intention of the so-called osteoanabolic drugs, not just to improve bone density, but to improve microstructure. And the way we think this happens is by a mechanism that I will discuss in the next slide or 2. Next slide. The fact it's right here. And I showed you this cartoon and now we're focusing on bone formation. The idea is that the drugs that we have available and hopefully, newer drugs that will be available in the future will have their primary focus to build bone. To build bone, these drugs will have to have important actions on the osteoblast that mononuclear cell in the arrow, you can see. And the primary mechanism, we think these osteoanabolic is to focus on improving bone formation metabolism and thereby help to restore that abnormal bone structure. Next slide. There are 3 drugs that we have classified as osteoanabolics. Teriparatide, of course, is PTH134, abaloparatide is an analog of PTHRP. And romosozumab is a completely different class of agents as an anti-sclerostin agent. These 3 drugs have been shown to be osteoanabolic and are available for clinical use in the United States. Next slide. And this last slide sets the stage for how we think these osteoanabolic work. The pink part of this slide shows you that early increase in bone formation. We actually determine this by work measuring bone formation markers. In the yellow line, you see subsequently an increase in bone resorption markers, which in a way helps to limit the anabolic potential of these drugs. And the difference in time course between the stimulation of bone formation and ultimately, the stimulation of one resorption, I and others have dubbed the anabolic window. It is a period of time when these agents are maximally anabolic. Now, as you all probably know, this increase in bone absorption is not necessary. It doesn't always match the increase in bone formation and it doesn't even sometimes change. And this is a topic of interesting discussion as we talk about the mechanism of osteoanabolic agents that we have now and the ones that are being developed in the future. Now, these are my introductory remarks. I'm pleased to hand the platform over to my colleague, Felicia Cosman, and she will give you additional information about anabolic agents.

Well, thank you very much, John, and good morning, everyone. It's a pleasure to be here this morning. I also am from Columbia University. I've spent my entire academic career there, actually began with John as my mentor during my endocrine fellowship, and I am currently Editor in Chief of the Journal Osteoporosis International and I have spent much of my academic career investigating the use of anabolic therapies. So it's really gratifying to be at this stage to be able to discuss this with you. Next slide, please. So as John so eloquently pointed out, patients with osteoporosis have problems with both the quantity of tissue in terms of bone mass being decreased as well as problems with the structure of bone tissue, microscopic structure. And our traditional approach to this has been to start patients on antiresorptive therapies, bisphosphonates are the most commonly used to try to prevent more deterioration. Next slide. The difference between anabolic agents and antiresorptive agents. In terms of anabolic agents being able to promote bone formation is that they improve the massive tissue really dramatically. And they also repair the microscopic architecture. And antiresorptive agents cannot do this, as John pointed out. And as a result, anabolic agents reduce fracture risk faster than antiresorptives. What you see here is our most potent antiresorptive drug denosumab on the left and one of the anabolic agents, abaloparatide on the right. And with denosumab, you can see that at 18 months, there's barely any difference between the treated group and the placebo group. And in contrast with abaloparatide, there's already a significant reduction. This is nonvertebral fracture risk, a significant reduction of 43% at 18 months. So much faster effect. And the magnitude of the effect also differs. The relative risk reduction for abaloparatide versus placebo being more than twice what we eventually see with denosumab in half the amount of time. Next slide. The most important studies which compare anabolic and antiresorptive agents are the ones that are head-to-head trials of the 2 different types of drugs. And the first of these was the VERO trial. This teriparatide in blue with risedronate the active anti-resorptive agent in purple in patients with severe osteoporosis in a head-to-head randomized study. And you can see that in 1 year and in 2 years, there was a significantly lower risk of vertebral fractures with the anabolic teriparatide compared to the antiresorptive resident. Next slide. This is also true when you look at the occurrence of clinical fracture or nonvertebral fractures, specifically, a 50% reduction in all clinical fractures is seen with teriparatide and a 34% reduction in nonvertical fractures, which just missed statistical significance. With teriparatide compared to the active drug, risedronate which itself, of course, reduces the risk of all of these fractures. Next slide. We also have a head-to-head comparative study of anabolic versus antiresorptive treatment in the ARCH study this looked at romosozumab in green versus alendronate in pink, showing at 1 year and 2 years, almost 50% reduction in the occurrence of vertebral fracture in patients who began with romosozumab compared to the active alendronate treated patients. Next slide. And this is also true in patients who began with romosozumab. The risk of nonvertebral fracture was 19% lower and the risk of hip fracture was 38% lower in patients who began with romosozumab compared to those who began with alendronate. So clearly, the anabolic agents are overall more effective at reducing fractures and faster at reducing fractures compared to active antiresorptive therapy and, of course, compared to placebo. Next slide. In addition to these fracture trials, we also know that BMD is very important. And a large project that's called the FNIH Sabre project has investigated multiple different types of treatments, almost 20 different treatments, 38 different clinical trials and has determined that the magnitude of the game that you get in BMD with osteoporosis therapy is associated with the degree of its anti-fracture efficacy. And to that end, starting with an anabolic increases BMD more than starting with an antiresorptive. Next slide. You can see that very clearly, again, in the ARCH study that shows romosozumab in green and alendronate and pink the BMD gain at 1 year is more than twice in the spine and in the hip, what you see with romosozumab compared to what you see with alendronate. Next slide. And this is also true with abaloparatide, where you see in orange here or brown, the gain with abaloparatide at 18 months, approximately being much larger than the gain that you see with alendronate in gray for 2 years from months 18 to 43 and the sequence of abaloparatide followed by alendronate produces large BMD gains which cannot be obtained with antiresorptive therapy alone in this period of time. Next slide. So clearly, what we have determined in the last 10 years or so, is that anabolic agents improve both bone mass and structure and both are involved in the ability of anabolic agents to reduce fractures very quickly, and they reduce fractures faster than antiresorptives and to a greater extent than antiresorptives. And in addition, the anabolic agents improve BMD more than antiresorptives and that BMD gain is associated with the fracture reduction effect. And as a result of all of these findings, we have all of our recent guidelines suggesting that anabolic agents be considered first for patients with severe osteoporosis and even for more moderate osteoporosis in some cases. So thank you very much for the opportunity to speak today. And I'm now going to turn this over to our colleague, Dr. Bart Clarke.

Good morning. This is Dr. Bart Clarke. I'm a Professor of Medicine at Mayo Clinic in Rochester, Minnesota. I've worked in this area along with John and Felicia for many years. And certainly, we have a number of considerations that even with all the drugs we have, there are still unmet needs for treating patients with osteoporosis. So next slide. So this one slide shows a summation of what currently is unmet need. And you might think that with the drugs we have, these are adequate. They may serve the purposes for our patients. But as Felicia has just gone over, there is still unmet need because of the perception that anabolic therapies are likely a better first approach than what we've used for the last 20 years. And so this one slide talks about these various issues. So the current issues in our field as we perceive them. First off, is that we need new orally active anabolic therapies. You may realize that the 3 anabolic agents we have currently that Felicia and John, both discussed, these are given by injection only at this point. 2 of those agents are given by daily self-injection like insulin. The other third agent is given at infusion therapy centers, typically in hospitals as a monthly injection. So having an oral agent available therapy would be a great boon to our patients who otherwise would much rather not take injections and still get the anabolic benefit as has been described. At this point, other oral agents would also be more effective than intravenous or injectable therapies. These are currently used clinically because we have no better choice and they're adequate, like I said, but at the same time, they don't work as well. And they don't raise the bone density as quickly and reduce fracture risk as quickly as these anabolic agents do. There is a lot of interest right now in terms of the sequence or combination of anabolic with or without antiresorptive therapies, you might think that using an anabolic agent first, followed by some antiresorptive agent would be a reasonable way to go, and that certainly is under evaluation at this point with various investigative studies. But otherwise, it might also be possible to use 2 anabolic agents sequentially. And so the choice of what we use oftentimes is limited by how the medicine can be given. And like we said, oral agents, we need desperately to treat these patients and to do the job that we're trying to do. Other issues that come up with this, you might imagine, compliance with all medications is generally dismal. Patients don't either take them as they should or they don't persist to take them. And of course, the benefits to be had for any disease condition are limited by either non-compliance or incomplete compliance and then lack of persistence. This also applies to our osteoporosis therapies. The biggest need, as we have said at the beginning of this talk is that if we had orally active agents that could be used for anabolic effect, this would be a great benefit to our patients and change the field actually and patients instead of taking injectable therapies would more often take oral agents because they work so much better. I'll stop here with this one slide and transition over to Miranda.

Okay. Thank you very much, and I'm very happy to introduce Entera Bio to you. Next slide, please. So Entera Bio is a leader in the delivery of peptides and therapeutic proteins in oral form, tablet form. And we focus on high unmet medical needs where we believe that providing a daily tablet as a peptide or therapeutic protein can meaningfully change the disease paradigm, the way patients are treated. We were founded in 2009 in Jerusalem went public and are listed on NASDAQ since 2018. We have 2 proprietary clinical-stage compounds, both looking at PTH, oral formulations of teriparatide, the exact same amino acid sequence as FORTEO, which was approved in 2002 by Eli Lilly, and we also have a preclinical strategic partnership looking at metabolic targets with Amgen. So the subject of and focus of today's talk is EB613, EB613 is positioned as the first oral tablet form of teriparatide. Again, the same amino acid sequence as FORTEO and positioned as the first oral anabolic agent to treat osteoporosis. In 2021, we completed our Phase II dose-ranging study and met all primary and secondary endpoints, including biochemistry markers of bone formation and resorption P1 and PMC TX, respectively, as well as 6-month BMD looking at lumber pine total hip and femoral neck. That was the subject of an oral presentation at ASBMR in 2021. We recently, in July of this year, publicly announced that we have submitted to the FDA our Type C briefing documents based on the guidance from the end of our Phase II meeting to design a placebo-controlled study looking at EB613 versus placebo and have an agreement with FDA to potentially look at total hip BMD as our primary endpoint, and we're expecting to update the Street on that at the end of the year. Our second clinical candidate is EB612, which, again, is an oral tablet form of teriparatide, which is being looked at for the treatment of hypoparathyroidism, which is an orphan disease. We have received open drug designation in both the U.S. and the EU. We did read out a positive Phase II pilot study in 2015, which met again, the very clinically meaningful endpoint of reduction in calcium supplementation and maintenance of phosphate levels. And we are currently reformulating EB612 to potentially decrease the administration from full-time day to twice a day, and we are going to go back into the clinic with EB612 in the beginning of 2023. Next slide, please. So we leverage on a proprietary oral delivery platform. And as most of you know, delivery of proteins or macro molecules is very challenging due to the enzymatic degradation and the GI tract variable drug exposure and pool absorption or bioavailability. So we simultaneously use proteus inhibitors and other excipients to increase the stability or create the maintenance of stability and the GI tract to maintain the integrity of the protein and simultaneously also use a peptide -- increased the peptide absorption into the plasma via the use of snack, which is a transcellular transport in Hansa in order to achieve therapeutically relevant levels in the bloodstream of the proceed. Next slide, please. So we're going to focus again on EB613, again, positioned as the first oral tablet of teriparatide. Next slide, please. As our distinguished panelists have already gone through BMD is routinely used as both a diagnostic means to classify osteopenic or osteoporosis patients as well as the patient management tool and the T-score basically looks at varying degrees of risk of fracture high-risk osteopenia is typically simply treated with vitamin D and calcium supplements. High-risk osteoporosis tends to be designated when T schools fall below 2.5% and up until minus 3 without a history of fracture and very high risk of osteoporosis designated when patients have T-score of negative 3 and prior fractures. It's estimated by a number of references, including our own pre-commercial survey work that we conducted that about 40% of osteoporosis, currently treated patients fall into that high-risk osteoporosis category, having T-scores of minus 2.5 to 3 without a real history of fracture. Next slide, please. This is, again, just one slide snapshot at the current treatment paradigm. So as again, was previously mentioned that the 2 main treatment categories fall into antiresorptive drugs, of which the most commonly used are [indiscernible], which do present oral daily, weekly, monthly. I need to know once-a-year injectable alternative and also most commonly used is the Amgen and [ anabolic ], Prolia, which does enable once every 6-month mode of administration. On the anabolic side, we have the 3 approved agents for abaloparatide which is subcutaneous injection of paid Tymlos, which is again, a PTH receptor activation, which is a daily subcutaneous injection and event anti-sclerostin antibody of Amgen, which is dosed once a month. There are currently no anabolic bone-forming agents approved, and each of these do require injections. And we believe that EB613 coming in again with the exact same sequences for [ tale ], we're not reinventing the wheel. We are simply providing patients that are reluctant to once they've cycled through the benefits of antiresorptive therapies are reluctant to get on to an injectable therapy. And so really they have hit a place where they have one or multiple fractures. Next slide, please. And with sales of current products and again, precommercial surveys are telling us is that currently, even with the very referenceable benefit of anabolics bone-forming agents in full the treatment of osteoporosis, they currently comprise less than 10% of treated patients. And as you can see, this fascinates really represents over half of the treatments used. Again, this is consistent with what the clinicians have previously voiced. My slide, please. We believe that EB613 has a unique role in potentially transforming the paradigm as the first oral tablet form of teriparatide. This is an incredibly validated mechanism of action with FORTEO leading and having been on the market since 2002. We do believe, based on clinician and market pre-commercial research that approximately 40% of the 3.2 million treated osteoporosis patients in the U.S. are full into that high-risk group with declining T-scores and as they cycle through their antirust therapies are reluctant to take daily injections until they experience fractures. And we also believe, and based on actually conversations even last week and a big debate at the ASBMR Annual Conference that health care providers given the data of induction therapy with anabolics would support the use of anabolics earlier in the treatment paradigm. So thank you very much, and I'm going to turn it over to Art Santora, our Chief Medical Officer, to go through our Phase II dose-ranging study results.

Thanks a lot, Miranda. The next slide, please, illustrates the design of our Phase II study. As Maria has been presented at the American side for bond Mineral research. The patients were subjects, I should say, enrolled in the study were premenopausal women with low bone mass. Those with severe osteoporosis proceeding, precluding the use of placebo were excluded from the study. It's a dose-range study using doses up to 2.5 milligrams daily. And the 2.5 milligram daily included both a titrated and a non-titrated group. A titration was done to minimize the risk of well-known [indiscernible] symptoms that have been shown with FORTEO and abaloparatide. The endpoints of the trial were assessed first at 3 months using P1NP, a market boom formation. However, it's very important to look at the BMD changes from baseline at 6 months, the most important secondary efficacy endpoint at 6 months and throughout the study, bone formation marker P1NP and bone resorption markers, CTX were also evaluated. The next slide illustrates the key changes. First, on the left, I'll show you the bone marker changes. The top curve illustrates the change in bone formation P1NP, the prompt increase at month 1 to about 30%, followed by a gradual decline over 6 months of treatment. Equally more important and -- equally important and really unanticipated was that the marker of bone resorption, serum CTX actually declined initially at month 1, but also remained lower throughout the study. The difference between formation, P1NP and resorption serum CTX is what's called the anabolic window. As long as formation exceeds the change in resorption, which it did throughout the 6 months of observation, a BMD change would be anticipated. -- shown on the left -- on the right panel is the actual change in lumbar spine BMD over the course of the study. There's a significant dose-related increase through the top dose of EB613 2.5 milligrams. The next slide illustrates all 3 key osteoporosis sites that is on the left, I just showed you the 6-month lumbar spine. But on the right panel, lumbar spine bone marl density, including both titrated and non-titrated significant increase versus placebo and unanticipated, but equally important was the fact that femoral neck and total hip BMD also increased substantially over the 6 months of treatment. This is in contrast to the effects of FORTEO in other clinical studies of FORTEO in which minimal or possibly not significant changes in total hip and femur BMD have been observed. The key takehome is that the lumbar spine BMD response was similar to that reported for FORTEO and a greater impact on thermal Mac and total head BMD were observed versus prior studies involving subcutaneous injected FORTEO. The next slide is the summary of safety -- observed spend profile was very similar to that observed with FORTEO. Typically, symptoms of orthostatic hypotension. EB613 was not associated with either serum calcium increases or hypercalcemia adverse events. Greater than 90% of subjects tolerated the 2.5-milligram titrated dose quite well throughout the end of -- through 6 months of treatment. And as noted, the commonly drug-related adverse events were very similar to those that have been reported for parenteral FORTEO. They were headache, nausea, presyncope, there were no serious or related adverse events in the trial. The next slide illustrates our proposed Phase III clinical trial design. Now patients recruited into this trial would be postmenopausal women whose BMD T-scores clearly within the osteoporotic range. But as this is a placebo-controlled trial, patients with severe osteoporosis, for example, multiple vertebral fractures, hip fracture would be excluded due to the use of placebo. Treatment proposed would be a total of 24 months. The first 18 months of treatment would include EBP05. That's the formulation name for EB613, 2.5 milligram dose, it included with titration versus placebo. And the final 6-month period would be a switch of all patients, drug-impacted to alendronate, similar to what's been done was done with the abaloparatide Phase III study. The primary endpoint would be based on change in BMD assessed at the total hip as is the target site and that the changes have to exceed predefined thresholds that Dr. Cosman alluded to called significant treatment effect. Secondary endpoints include changes in BMD throughout the study and [ bone turnover ] biomarkers. So I'd like to turn the discussion back to Miranda led by, I guess, Tara’s coordinating for questions from those who called in or submitted questions. Miranda?

Great. Thank you. At this time, we will be conducting a question-and-answer session with our speakers. [Operator Instructions]. Before we kick off questions from the audience, I'd like to ask the KOLs a question. Can each of you describe in your view, the potential for EB613 as the first oral anabolic and first oral PTH treatment for osteoporosis. And how do you expect to shift the treatment landscape?

Please, Felicia.

Yes, I'd love to start because I'm really excited about the potential. I myself have been involved in the development or the attempted development of multiple other products over the last 15 years that have not gotten to this stage, looking for oral or transdermal delivery. We know as Dr. Clarke pointed out that one of the big problems with our anabolic agents is that patients don't want to take them. And that's true even if they've had fractures, they don't want to take them. And it's understandable, daily injection, a monthly injection can be difficult. An oral formulation of an anabolic compound has tremendous potential to be favorable to a broader group of patients, both with severe osteoporosis and more moderate levels of osteoporosis and could have a really big impact on the treatment of this disease.

I'll just comment that in clinic these days, many times the choices between which injectable to take because we have no other choices that are effective. The patients recognize the advantage of the anabolic therapies in principle, but the problem is it's either a daily injection or a monthly injection for somewhere between 1 and 2 years. And most patients will say, "I'd rather take something less frequent." Oftentimes, the choice is made for a less frequent dosing, 6 monthly injections, for example, as the fallback option, even though that particular agent is a good agent, but it's not as good as the other options. And if we have the option of giving patients 2 tablets a day, this would be a very big seller, and I suspect it would be used widely, maybe perhaps even by more than the patients for whom this is actually getting approved, those with high-risk or very high risk of osteoporosis.

No, I would just echo what Felicia and Bart said. I'd also add, though, that when we think about oral agents for osteoporosis, we really are doing very well, even when we consider the antiresorptives because of all the so-called baggage that the bisphosphonates carry. So not only would this change the paradigm in terms of anabolic therapy, namely going from injectable to oral, but also provide the field with let's hope that things work out the way one hopes they work out with an oral agent that is shown to be safe or [ not vacations ]. So I think this has a really broad implications for the whole therapeutic area of osteoporosis, not just anabolics.

Great. Thank you, everyone. So we'll now begin taking questions from the audience. Our first question comes from Boobalan Pachaiyappan from H.C. Wainwright.

Can you hear me okay?

Yes.

All right. Great. Thanks for the great presentation, doctors. The background slides were highly informative. So I have some questions about background slides and then a few on EB613. So firstly, with respect to bone strength because this has been featured multiple times in today's talk. So just curious, do we have sufficient tools to reliably and adequately measure bone strength. As you know, the DEXA scan, it creates 2-dimensional images. So do you think that those 2-dimensional images adequately capture the bone structure?

So the data that we show in terms of fracture efficacy are already the ultimate indicator of improved bone strength. You cannot reduce fracture risk without improving bone strength. So we've shown that in the clinical setting with these fracture endpoint studies. But I think really key to the last 5 years or so in our field has been the large studies that have shown from this FNIH project, a public-private partnership that BMD gains while they may not reflect the entire story with our treatments are highly predictive of the effect against fracture and are an indicator of improvement in bone strength. We do have, of course, other surrogate measures of bone strength through QCT determinations that support this. But it turns out that we actually don't need anything beyond the hip and spine BMD endpoints to know that we're improving those trend.

It's interesting. We've gone from skepticism about on density as a marker is [ colitis ] of on strength and many different technologies are available. And I believe the Phase III in the sub-study will probably avail itself but we've come back. We've come back to bone density as the easiest, most practical and actually the most direct way of predicting bone strength and fracture reduction. So it's a very interesting historical backdrop here. We've come full circle. And now we don't know what the FNIH project that we don't have the final word on the acceptance of bone density as a surrogate marker, but many of us are hopeful because as Felicia says, it probably is the best way to go for these clinical trials that have a placebo control.

Certainly, there are ways to get that information in terms of either high resolution, peripheral quantitative CT scanning, that's a long term, but Felicia mentioned quantitative CT scanning. That's historically how we've done this. Alternatively, in some studies, of course, historically, they would do bone biopsies looking specifically for microarchitectural change. So if it's needed to be obtained, it can be, but as Felicia says, the field has come back to the bone density actually being probably our best instrument because it captures not just fracture risk, but in that fracture risk assessment is capturing the microarchitectural changes even though they're not documented.

Great. And then secondly, with respect to the goal of treatment in osteoporosis patients, so what is actually the goal? Is the goal clearly defined? Is it the factor prevention? Or is it increase in bone mineral density? And then in a slightly different topic, let's say, if you're going to focus on going neural density, what is the optimal T-score target for therapy? As most patients have anywhere between minus 2.5%, minus 3%. So what's the T-scores that we are looking for? Well…

I'll take that. Thank you. You asked what the ultimate endpoint is, obviously, it's to reduce fractures, but the reduction of fractures that can't be an endpoint because no fracture, there's not something you can measure but the point you raise is an important one, if bone density is to be used, what is the endpoint of the gain in bone density, we do have information from the denosumab trial, which very interestingly showed that as bone density improves, fracture risk actually goes down. But there is a resistance point between minus 1.5 and minus 2, beyond which further gains and bone density in that study were not associated with further reductions in fracture. So when we think about a drug and a target, I would think it's very reasonable taking someone with a T-score of minus 2.5 to minus 3 to look at a target like let's say, minus 1.5 to minus 2. Because at that point, you have reached the goal and there is no real point in further improving bone density beyond that threshold.

And I would agree with everything that John said and add that we also have data from the ARCH study looking at this with romosozumab and alendronate, that the BMD level attained at 1 year is predictive of subsequent risk of fracture. And once you get up to around minus 2, that curve starts to flatten. And so exactly what the target should be is still under discussion and actually an ASBMR-sponsored task force as we convened to address this issue over the next year. But most of us think, look, it has to be above minus 2.5. And for individual patients, we may want to try to attain a T-score of minus 2 or even minus 1.5. And that would be largely driven by total hip target and perhaps secondarily a spine T-score target as well.

Agree. I think it's premature to say definitively because we don't have the data yet, but that will come eventually. This task force will help sort this out.

Our next question comes from Matt Kaplan from Ladenburg.

Okay. Thanks for the presentations this morning, really terrific. I wanted to just focus on the topic at hand when we're talking about the FNIH and the ability to use BMD as a primary endpoint, what's your sense, I guess, from the panelists, when could this be really incorporated from the FDA, given what we know now and given the correlation, that's very, very clear that from these studies that's already been published.

I mean, I'll just jump in, if you don't mind. And I don't think anyone on this panel. I mean, I wish that someone on the panel had a crystal ball, but I don't think anyone has one. And I think we can only look at what's been publicly stated in the website of the FNIH and then FDA and public -- in press release is basically consistently saying that they plan to have a full review of the FNIH package by the end of 2022. I don't think more than that other than checking the website can be said, but I'll open it up to others.

There were a number of questions for the NIH officers at the meeting at ASBMR now roughly a month ago or so. And of course, they were very cryptic in what they responded because they said they couldn't tell because other people were making those decisions. So even the bone people who are the experts in osteoporosis at the FDA, they weren't sure. So we really can't say much.

And then just the -- maybe a comment on the Phase II data for 613. What was pretty interesting to me was the results across the board in terms of impact on BMD all substantially increased. Maybe can you comment on the results there that they had with respect to the femoral neck and the total hip BMD and the differentiated results from the historical from FORTEO given it's essentially seen ingredient?

I would just jump in and say that those results are very interesting, as you may imagine, to us, the company, and we are currently because we have this pronounced effect on total hip BMD and femoral neck BMD in contrast to previously reported data for FORTEO. We are currently looking at doing a preclinical mechanism of action study looking at fluoro scan actually. And that's also because as you previously noted, our biochemistry also is a little different from teriparatide in that we have this increase in P1NP, the marker of bone inflammation, but we also have simultaneous or a decrease in CTX, which we actually -- which more closely resembles the pattern that you see for romosozumab. So we're actually conducting just for our own curiosity, mechanistic, preclinical. We're looking at mechanistic studies to try to answer that question. But right now, we just have the clinical data.

Just a comment about that. This is very interesting, and it does speak to how parathyroid hormone under certain circumstances can be catabolic, which is to say not good for cortical bone. And when you're dealing with the hip, it's a much more cortical favorite site, let's say, than the lumbar spine. The fact that with this product, there does seem to be a reduction in bone resorption might speak to a protective effect or mitigating that potential catabolic effect of PTH on cortical bone. So it actually fits with what we know so far. It is very interesting, and I think further work will help elucidate what the actual mechanism, but it would appear to be a different mechanism from teriparatide and from abaloparatide.

I'm not sure if Matt left the call, I just wanted to follow up on the FNIH criteria and timetable. I think we have -- I don't think we have publicly stated that we designate to total hip BMD as our primary endpoint, and that is within the reference publications of the FNIH and we also use -- sorry, get threshold endpoints that are correlated to vertebral, nonvertebral and old site fracture reduction because they are the highest level of scientific literature that we can use as an endpoint irrespective of FNIH getting qualified or not. I think our anticipation is that will be receptive to us using a very validated kind of scientific -- coming from the scientific literature BMD analysis in our primary endpoint.

Our next question comes from Andreas Argyrides from Wedbush.

I'll start with one for management and then the rest for the KOLs. So for management, can you provide more details on the factors that determine the timing of titration? And then for the KOLs, what about the bone turnover marketers make this product attractive? Where do you want to see the bone turnover markers settle towards? How are you thinking about long-term safety of this product is 24 months enough? And what is clinically meaningful increase in BMD in different sites?

So with respect to titration in the Phase II, we titrated up to the 2.5-milligram dose, which is the dose that we're carrying forward into Phase III over 2 months. So patients got 10.5 for the first month to -- and then 2.5 starting from month 3 in the titration protocol. So in essence, those patients were only on the full 2.5-milligram dose for 4 months after the full 6 months and not meaningfully reduced the AEs that we saw with orthostatic hypotension, very similar in nature to what you would expect from injectable are [ teriparatide ] and we understand that patients that sometimes start on teriparatide on portal, do skip injections until they normalize their safety, their adverse events. In the Phase III, where it's a much longer duration study, obviously, and we are potentially looking to accelerate the titration. So it's not over 2 months, but we're looking at different acceleration of the titration so that it's not taking such a long time to get to the 2.5 full dose. With respect to other questions, I'll leave it to the clinicians that can come back and also add to the answers.

So Andrea, as you've asked the questions that will take 15 minutes to answer. But thank you, Andrea, for the questions. So I'll just quickly try to address what you are getting at. The bone turnover markers with anabolics settled down to a new baseline, and the baseline is usually the old baseline. So I would predict as the bone markers are moving, they will eventually because there's a biological -- I think there's an internal biological control that the body has some wisdom about. So I think that will probably happen. Secondly, I think bone density, that's an open question because the change, the chronology of changes in nonmarkets do not always do not follow the chronology of changes in bone density. So I think there are 2 paradigms here. And I think it requires just more work, longer studies before we can sort this out.

I agree. And I think we've shown that this is clearly producing an anabolic effect by the bone formation marker going up. And the fact that there also appears to be some antiresorptive activity expands that so-called anabolic opportunity. It promotes a greater net potential gain in bone mass than you would see if the resort to marker actually increased. And that could have implications for improvement, early improvement in cortical bone. And the magnitude of the gains that we see just at 6 months is really -- are really consistent with effects that we might expect to see against both vertebral and nonvertebral fractures based on the findings from the large meta-regression study, the FNIH study. So we're very favorably impressed with the Phase II data so far.

And the importance of this clinically is that there's only one other drug in the history of the world that's been shown to do this. This drug stimulates formation at the same time it blocks bone resorption. The net effect of that, of course, on bone density will be to raise it more. But the only other drug that's ever been shown to do this was the most recently FDA-approved drug, romosozumab. And if it turns out, this is like that, this is a huge addition in a sense beyond what we thought this might do earlier on.

I'll now turn it over to Brendan Payne from LifeSci Advisors to read the remainder of the questions from the webcast.

Perfect. Well, thank you very much, Tara. Thank you, everyone, for this excellent dialogue. We want to afford some opportunity for investors who have submitted their questions independently as well. So clearly, the strength of the case for anabolics has been made quite strongly here. And yet Miranda, for presentation in the other product in commercial surveys indicate that less than 10% of patients at risk are on anabolics. In the context of EB613, specifically, can we attribute that to a version to the injection MOA? Or is there something else going on here as well?

I mean, I can only comment on what we've surveyed from clinicians and other ways. And that's basically -- there's a patient journey where patients are diagnosed with osteoporosis and need to start treatment. And as everyone said, they begin on antiresorptives and typically is [ fascinate ] for a few years, full 6, 7 years is not uncommon, then continue or startup also on Prolia typically 2 to 4 years. And then eventually, T-scores continue to deteriorate and all fractures happen. But more often, the T-scores are deteriorating. So that's basically resistance, they're cycling through the [indiscernible] option pool. And then there's a white space. And that was -- that's the white space I was referring to, which is this what's called by ACE criteria, high-risk osteoporosis where you have T-scores of minus 2.5 to about 3, and you don't have fractures. You don't have a visible disease. You don't have actual bones breaking and there's a white space because you cycle through the more easy-to-take options, the tablet [indiscernible] or the once-a-year is phosphonate or the once every 6 months for Prolia. And then you don't really want to get on something which requires daily subcutaneous injection or monthly if you're not seeing the symptoms, and that's what we're hearing. And so if you look at the profile of the patients that are currently on the osteoanabolics, which are all wonderful drugs with wonderful data, that the most of the patient population are there patients that have an experience, which leads them to, “Okay, I'm going to get on to the injector now to control my disease.” And so our thesis is with EB613, should it continue to perform as an oral teriparatide to really address this white space of patients, which are not high-risk severe with multiple fracture history and declining T-scores of negative 3.5 and down, but really serve the patients that have cycled through the antiresorptives and simply reluctant to get on to an injectable daily or monthly. So that's how we're seeing it, and I'll open it up to the panel.

Any further comments from any of our esteemed KOLs on this question specifically?

I just make some comment that you people know more than I. But I've been very disappointed in the marketing of the anabolics. And I think just fast forward, let's say, this drug meets all the endpoints and gets approved. That's not the ad story. The drug has to be presented to doctors and to patients in a way that is acceptable. And I do think that the genius of marketing if you have a good product, it goes hand-in-hand with the success of a drug.

Okay. Perfect. Well, thank you very much...

Let's just -- I would just say that even -- just to give a reference, even with the daily injection of FORTEO, the drug did reach $1.7 billion in peak sales globally with about $1 billion in the U.S. granted at a high price. So it was a very, very successful -- is a very successful product. We think that we have a price advantage because of our potential COGS. And we think we can cater to lowering the risk of fracture as a much wider population of osteoporosis patients. So we think that we could -- this drug has potential really to fill that white space. But for [ tail ] was a very big commercial success.

So clearly... The market is much bigger than what has been penetrated so far in terms of the clinical utility of the drug. And I think that the -- an oral formulation would just be so much more acceptable to so many of these patients, not just those who have failed other therapies, but those who are newly diagnosed in that minus -- below minus 2.5 range. Many of us think that almost everybody diagnosed with osteoporosis would benefit from a course of anabolic therapy to rapidly rebuild mass and microarchitecture. And the thing that's stopping that complete paradigm shift is the need to inject the available compound. So an oral formulation could make a really huge impact in which patients are considered for this therapy.

Perfect. That makes great sense. And a natural segue from that talking about the white space of Miranda and Dr. Santora talking about sort of the anabolic window. If we -- if EB613 was successful in moving treatment further up the patient journey, what do you think is the potential for an anabolic like this used earlier in the treatment paradigm? And what do you think the challenges to adoption of currently approved anabolic agents have been to get them used earlier?

Maybe I'll -- well, Miranda, go ahead. Sorry.

I'll just tell you what we think the numbers also. There is about 15 million osteoporosis patients in the U.S. There's about 3.1 treated and about 40% R&D, what is by its criteria, high risk. So T-scores minus 2.5 to 3 with no major fracture history, which, by the way, is the exact population that we treated in our Phase II dose-ranging study and the exact population that we plan on treating in the Phase III.

I'll just comment that you realize there is a treatment gap for osteoporosis like many other conditions where patients who should be on therapy either decline to take it or refuse because they're worried about side effects, costs, other issues. If we could expand the treatment space with people with osteoporosis from $3-some million to the $15 million that Miranda just mentioned, this would obviously open up the market in a large way because the perception of an oral agent is it's easier to take. And unless there's side effects, this is something that many people would be willing to take, whereas now they just won't.

Perfect. Now, if that's okay. I'll move on. Then for the benefit of our KOLs today who were able to hear Dr. Santora present the protocol and the design for the proposed Phase III trial. Do you have any thoughts specific about that protocol design that you want to speak to?

No.

Okay. Perfect. We can move right along. Can any of you speak specifically to the -- your thoughts on the NIH endpoint of total hip BMD and your view of the publication supportive of that endpoint? How do you think it will be received by the clinical community? And is it being talked presently amongst your peers?

Bart, do you want to take this?

Yes, sure. It is being talked about. People have heard of it, and this process started back maybe now must be at least 3 to 4 years ago. Some of our colleagues were working on this and gave updates on the progress. So the big thing is it was actually able to be submitted, it was accepted, and it's undergoing review as we understand it. The hope is that this would make it possible to show benefit from new antiresorptive or anabolic therapies without actually having to prove fracture benefit. This would save on cost and time. It would open up the market to a lot of other products perhaps that could be used for this particular area, therapeutic area that would be beneficial.

Felicia?

Yes, I agree. It's a really exciting time in our field, and we've been waiting for this really for a while, and we hope that it really will happen towards the end of this calendar year or early in 2023. And I think that the data supporting this not only include the large meta-regression analysis, but also the individual studies. John alluded to with denosumab and the Freedom trial. I mentioned the romosozumab and alendronate data from the ARCH trial. They really show that if you can get BMD levels up above that osteoporosis range, your fracture risk reduction is -- you have a much lower fracture risk moving forward. And of course, from the patient perspective, being able to measure this change and to receive this feedback that, in fact, we have made bone stronger and more resistant to fracture provides a very good feedback for patients to help with subsequent compliance and to help get other patients on this type of strategy.

Perfect. Thank you. Well, it's very exciting. And with that, in the time we have remaining, I'd just like to pass the call back to Miranda for closing remarks, but thank you all for this very encouraging discussion today.

Thank you very much to LifeSci for hosting this, and thank you very, very much to our esteemed advisers that were incredibly helpful hopefully to you as well today. And thank you for joining us. Have a good day.