Welcome to the Entrada Therapeutics conference call. I would now like to hand the conference over to your first speaker today, Karla MacDonald, Chief Corporate Affairs Officer. Please go ahead.
Good morning, everyone, thank you for joining us today. I'm Karla MacDonald, Chief Corporate Affairs Officer at Entrada Therapeutics. Today we will be reviewing the positive top line results from cohort 1 of participants living with Duchenne muscular dystrophy or DMD, treated with ENTR-601-44 in our phase I/II ELEVATE-44-201 study. Our news release, along with the accompanying slides, can be found in the investor section of our website. Before we begin, I would like to note that we will be making some forward-looking statements during our presentation within the meaning of the U.S. Securities Act of 1934. These statements are based on Entrada's current beliefs and assumptions, are subject to risks and uncertainties, and are not guarantees of future performance. We undertake no obligations to revise or update any forward-looking statements.
We encourage you to review our SEC filings for more information. Speaking on today's call are Dipal Doshi, our Chief Executive Officer, Dr. Natarajan Sethuraman, our President of Research and Development, and Dr. Laurent Servais, Professor of Paediatric Neuromuscular Diseases at the University of Oxford. Dr. Servais is an expert in the treatment of DMD and other neuromuscular diseases and serves as an investigator in our ELEVATE-44-201 study. We are thrilled to have him on the call with us today. Nathan Dowden, our President and Chief Operating Officer, and Kory Wentworth, our Chief Financial Officer, are on the line to answer any questions. Turning to today's agenda, Dipal will begin with an introduction and overview of our development strategy for our DMD franchise. Dr. Servais will discuss the urgent need for new therapies for people living with Duchenne.
Following his remarks, Natarajan will review the cohort 1 top line results and outline the next steps for our ELEVATE-44-201 study. Dipal will conclude by reviewing the upcoming clinical milestones across our pipeline before opening the call for questions. I will now turn the call over to our Chief Executive Officer, Dipal Doshi.
Thank you, Karla. Good morning, everyone, and thank you for joining us. Today marks an exciting and important moment for Entrada. We are incredibly pleased to share positive top line results from cohort 1 of our phase I/II ELEVATE-44-201 study evaluating ENTR-601-44 in ambulatory individuals with a confirmed mutation in the DMD gene amenable to exon 44 skipping. This is the first data readout from this important clinical trial, and we are encouraged by the results we have seen to date. We are also honored to be joined by Dr. Servais, who will provide clinical context for the data we are sharing today. Taking a step back, Entrada is a clinical stage biopharma company developing proprietary genetic medicines to deliver best in class outcomes in high unmet need diseases.
As we look at the year ahead, Entrada is positioned to have a milestone rich 2026. We have a deep and expanding pipeline with multiple value inflection points in 2026, including 4 clinical catalysts in DMD and DM1, with additional pipeline expansion efforts ongoing. Our programs are differentiated in untapped markets. Notably, in our DMD program, we are pursuing an accelerated approval strategy in a market with profound unmet patient need. Additionally, our ENTR-601-44 program has progressed to the second cohort at the increased dose of 12 mg/kg at the recommendation of an independent data monitoring committee. Today's cohort 1 data, our ELEVATE-44-201 open label period data, as well as the cohort 2 data by year end 2026, have the potential to de-risk and establish proof of concept across our neuromuscular programs.
With the cash runway into the third quarter of 2027, we are well capitalized to realize our value catalysts. On slide 6, our efforts to establish a new class of genetic medicines have enabled us to build a growing and diverse pipeline of therapeutics focused on disease areas with a substantial patient population and a significant unmet medical need. Specifically, we're pleased to share positive top line results from cohort 1 of the ELEVATE-44-201 study. Natarajan will dive deeper into the data, at a high level, results demonstrated a favorable safety and tolerability profile and meaningful, potentially differentiated functional benefits in participants treated with ENTR-601-44. We're on track to report data from the open label period and from cohort 2 at 12 mgs per kg by the end of the year.
In December, the FDA also granted rare pediatric disease designation to ENTR-601-44. We are also currently dosing patients in our ELEVATE-45-201 study and expect this to be both a best in class and a first in class program to meet the needs of a large segment of the DMD community. We expect to deliver data from cohort 1 in mid 2026. Our ENTR-601-50 candidate received regulatory authorization from the U.K.'s MHRA and Research Ethics Committee. For both ENTR-601-50 and ENTR-601-51, we expect to submit additional regulatory applications and obtain authorization following a review of data from the ongoing studies of our lead programs. Our partners at Vertex continue to enroll and dose the MAD portion of the GALILEO global phase I/II clinical study of VX-670 in people with DM1.
The study assesses both safety and efficacy and is on track to complete enrollment in dosing in the trial and share results in the second half of 2026. Beyond the strong progress in our clinical programs, we've generated positive preclinical data for programs focused on ocular and metabolic diseases, which include new moieties. This includes the advancement of two novel oligonucleotide-based programs for the potential treatment of inherited retinal diseases where there is a high unmet need. The first ocular candidate, ENTR-801, an exon 13 skipping therapy targeting a subgroup of patients with Usher syndrome or Usher 2A, was announced in December 2025. We expect to name a second clinical candidate in an ocular disease in the second half of 2026.
On slide 7, I will now turn the call over to Dr. Servais, who is a professor of pediatric neuromuscular diseases at the University of Oxford, current President of the World Muscle Society, and serves as an investigator in our ELEVATE-44-201 trial. Dr. Servais will discuss the urgent need for new therapies for people living with DMD and what the initial cohort 1 results mean for the DMD community.
Thank you very much, Dipal. Before going into what is actually Duchenne muscular dystrophy, I would like to show you one of my patient with this condition. He's 4 and a half years old, and as you will see, he has a lot of difficulties to climb stairs. He would like to do it as fast as possible, but he needs the banister. He needs to push on his leg to be able to climb the stairs. We know that unfortunately things are not going to be better with time, and this proximal weakness will be more and more obvious with time and this young boy unfortunately will lose the ability to climb stairs and to rise from floor, eventually will lose ambulation between the age of 10 and 20.
Duchenne muscular dystrophy is related to a mutation into the dystrophin gene, and the dystrophin gene codes for protein that is called dystrophin, and dystrophin is a giant. It's a very big protein, and it's actually the shock absorber of the muscle cell, but not only. Yes, the main function is shock absorbing, but also it binds with several very important protein, and that's why it is that important if we try to restore dystrophin to try to keep the main domains and eventually to get the longest dystrophin as we can when we try to restore dystrophin. You know what happen in a car if you don't have a shock absorber? It breaks, right? The very same applies to a muscle cell.
If a shock absorber is missing, the muscle cell can be destroyed and then you have a process of necrosis and regeneration that characterize dystrophin dystrophy in general. So fortunately we have stem cells that can multiplicates and give a new muscle cells, but unfortunately the genetic defect is also present in the stem cells, and you have a kind of very accelerated turnover of the muscle cells. The problem of Duchenne muscular dystrophy is that it affects all muscle, including heart, right? The burden for the family, for the kids of course, but for the family and also for the society is huge. It starts with contractures, and that needs physiotherapy and sometimes even orthopedic management.
Those kids will need mobility support like a wheelchair. Because of the steroids they will have endocrine issues and because of steroids and because of the immobility, they could have bone health issues. Because of the weakness they can develop with scoliosis, insufficiency to ventilate and then respiratory issues. Some of these kids may also present with cognitive issues and eventually heart problems. It is a very complex condition that will represent for the family and for the society a very significant burden.
It's very interesting to figure out that some patients may have a slightly milder phenotype and lose ambulation 4 to 5 years older than the others, and those are the patients who are capable for the 44. Why do these patients present this difference in loss of ambulation is because they naturally express 5% of dystrophin. We know that if we could express something like 5% of dystrophin, and if we could do it since birth, then we could be potentially instrumental on the loss, the age at loss of ambulation. If we can express more than 5%, it will make a lot of sense for the patient and for the family.
That's why I think it's very exciting to see products that even at a low dose may induce a significant exon skipping and some dystrophin expression, which is in line with the exon skipping that is observed. Of course, we need a longer exposition to the drug because we also know that with time, the amount of dystrophin that is expressed by drugs that promotes exon skipping will increase. I'm very excited with the fact that escalating the dose could allow to improve more exon skipping and more dystrophin in these boys. Thank you for your attention.
Thank you, Dr. Sureau. We very much appreciate your continued support as we advance our clinical programs in DMD. Today, I'm very excited to share the topline results from cohort 1 of our ongoing ELEVATE-44-201 trial. First, let me go through key takeaways from our data. We met the primary objective of the study with favorable safety and tolerability of ENTR-601-44 at 6 milligrams per kg dose. All 8 patients have transitioned to open label portion of the study. Markers of kidney function were within normal range and comparable to placebo. We were surprised and highly encouraged to observe earlier than expected functional responses. A statistically significant improvement in treated participants time to rise velocity versus placebo. Time to rise velocity is an approvable clinical endpoint in phase III studies.
We have seen positive changes in TTR velocity across the majority of participants, irrespective of the severity of the disease or age. We have also observed lower than expected plasma exposure and consequently lower dystrophin levels in pediatric DMD patients when compared to the exposures we have seen in healthy adult volunteers and adult NHP. This, however, is consistent with the exposure data we recently received from our juvenile NHP studies. We have updated our PK modeling and believe the plasma exposures will be significantly increased in cohort 2, resulting in higher muscle concentration, exon skipping, and dystrophin production. We believe we have a highly differentiated delivery mechanism, including ability to access quiescent satellite cells, which are critical drivers of muscle regeneration and repair. This unique mechanism of action may explain why dystrophin levels in cohort 1 were sufficient to improve time to rise velocity.
Ultimately, the goal of any therapy is functional benefit, and that is why these early results with ENTR-601-44 are uniquely important. Now, I would like to provide some background on our drug candidate, ENTR-601-44, which is an investigational genetic medicine, and review the trial design. ENTR-601-44 is designed to address the underlying cause of Duchenne, facilitating the production of functional dystrophin from mRNAs with corrected reading frame. ENTR-44 is a proprietary Endosomal Escape Vehicle conjugated oligonucleotide. The oligo sequence is optimized for skipping exon 44 for patients with a mutation in the DMD gene that is amenable for exon 44 skipping. This comprises approximately 8% of the Duchenne patient population globally. ELEVATE-44-201 is a global, 2-part, randomized, double-blind, placebo-controlled phase I/II study evaluating the safety, tolerability, and effectiveness of ENTR-601-44 in ambulatory participants ages 4 to 20 who are exon 44 skip amenable.
Multiple ascending dose, part A portion of the study, evaluates the safety, pharmacokinetics, pharmacodynamics, and functional parameters following intravenous administration of ENTR-601-44 to study participants in U.K. and E.U. There are 3 cohorts in the study. Today, we will be talking about cohort 1 results, and the cohort 1 portion of the study enrolled 8 participants ages 6 to 17. They were randomized 3 to 1 to receive ENTR-601-44 at a dose of 6 milligrams per kg or placebo administered through intravenous infusion. During this double-blind period, doses were administered on days 1, 43, and 85. Muscle biopsies were performed at the time of screening and 6 weeks post the last dose. Following the initial 3-dose administration in part A, all participants continued to the phase II portion, or open label portion of the trial, for evaluating safety and efficacy over longer period of time.
This study is designed to enable registrational conversation with the FDA, leveraging the accelerated approval pathway. Future phase III confirmatory studies are expected to enable full approval in the U.S. and beyond. Let's look at the demographics on baseline characteristics of cohort 1 participants. The average age of treated participants in the study was 9.3 years. Per protocol, all participants were ambulatory, all were on stable doses of steroids. Baseline dystrophin in both placebo and treated population were lower than what has been reported for other exon skipping clinical studies. This is important to note, as dystrophin increases after treatment generally correlate with higher baseline dystrophin levels. Let us look at the safety data. We saw very favorable safety and tolerability, the primary endpoint of our study with ENTR-601-44 at 6 milligrams per kg.
All patient treatment emergent adverse events, or TEAEs, were mild to moderate, with most common AE being headache. There were no reported serious adverse events, or SAEs, and no adverse events leading to discontinuation from the study. No renal safety concerns were observed in the study participants who received ENTR-601-44. All 8 cohort 1 participants have now transitioned to open label portion of the study. We are pleased to see markers of kidney function, including eGFR, cystatin C, and magnesium, were in normal ranges and comparable to placebo, reinforcing the strong safety profile of ENTR-601-44 in patients with Duchenne at 6 milligrams per kg dose. Let's change gears and review the PK and biomarker data. We observed a lower than expected plasma Cmax and AUC, or area under the curve, in pediatric DMD patients.
About 50% less than levels seen in healthy adult volunteers and healthy NHPs. This, however, is consistent with the recently received PK data in juvenile NHPs. In juvenile NHPs, there was more than dose proportional increase in plasma AUC at high doses. We believe that the low plasma exposure at the starting dose of 6 milligrams per k in cohort 1 resulted in lower exon skipping, about 2.3% above baseline, and dystrophin levels, about 2.3% above baseline in pediatric patient population. As I mentioned before, the baseline dystrophin was lower in 1 patient than what we had reported than what has been reported in other studies. At day 127, 6 weeks post the last dose, the dystrophin level in treated patient was approximately 6%.
While we were surprised to see significant differences in exposures between juveniles and adults, the consistency seen between NHPs and humans fully explains the difference and gives us confidence that we will see meaningful plasma exposure in cohort 2, which we expect will deliver higher exon skipping, higher levels of dystrophin, and sustained gains in muscle function. We originally projected PK and exon skipping based on adult human normal volunteer study because that was the only human data available at the time of cohort 1 dose selection. Data from juvenile NHP study did not become available until the end of the 1st quarter of 2026. Thus, at the time of cohort 1 design, the adult normal human volunteer study and adult NHP data were the best available anchors for human PK projection, and this is not unique to Entrada.
Now that we have both cohort 1 patient PK data and juvenile NHP data, we have right-shifted our projections. The juvenile NHP data reinforces the lower initial AUC set point in ENTR subjects and suggests that we will see dose-dependent increase in AUC. More importantly, juvenile NHP data also shows a steep non-linear exon skipping response at higher AUC levels, suggesting cohort 2 will see a disproportionate increase in exon skipping to the dose increase. This gives us much more relevant basis for cohort 2 and cohort 3 projections than the adult data provided for cohort 1. Our updated PK analysis projects higher levels of plasma concentration, exon skipping, and dystrophin in cohort 2 and cohort 3, supporting our path to accelerated approval and eventually full approval.
The DMD community at large continues to learn about the biology of Duchenne and the relationship between dystrophin and functional benefit. Despite lower plasma exposure and dystrophin level, we obtained earlier than expected functional response that was statistically significant, which we will go through in the following slides. As I mentioned, the ultimate goal of any therapy is functional benefit, that is why we are so encouraged to see earlier than expected functional response that were both statistically significant and clinically meaningful. Let me give some background on time to rise functional assessment. PTR is a measure which carries the largest absolute and proportional annual signal and is used as an early prognostic factor for disease progression and loss of ambulation. It is generally the first functional metric to respond to therapy and has good statistical properties for evaluating motor function in individuals with DMD.
Rising from the floor engages most of the proximal muscle groups that fail earliest and most dramatically. PTR velocity is expressed as traces per second and is designed to reduce the impact of outliers. With that background, in cohort 1, we have shown statistically significant improvement in treated patients' time to rise velocity versus placebo. The mean change of PTR velocity was 0.08, 3.5 times higher than minimal clinically important difference or MCID threshold of 0.023, suggesting that ENTR-601-44 is potentially changing the trajectory of the disease. Positive change in PTR velocity was seen across majority of the participants irrespective of the severity of their disease or age, which likely suggests that cohort 1's functional benefit is drug-related effect.
The end of cohort 1 dystrophin level correlated with the end of cohort 1 PTR velocity, suggesting that dystrophin production may have crossed a critical threshold for functional improvement. Additionally, we have also seen a positive trend in 10-meter walk/run assessment, another metric used to evaluate motor function in DMD. It is important to note that PTR velocity is recognized as an approval phase III endpoint in DMD clinical studies that has been and is currently being used by companies. We are already generating clinically meaningful functional benefit at the lowest dose tested in the study, and the PTR velocity we saw in cohort 1 data is unprecedented.
PTR velocity, treatment difference of 0.115 rises per second is nearly 2 times, or to be accurate, 1.7 times compared to what was seen with pamrevlumab signal that the FDA accepted as a registrational primary endpoint at 0.06 rises per second in their VISION-DMD study. The fact that we achieved statistical significance with just eight participants at the lowest planned dose leads us to feel confident that we will see further functional benefits as we dose up in cohort 2 and 3. Let's now dive into why we believe a highly differentiated delivery mechanism with ENTR-601-44 could lead to these differences. DMD progression is driven by both aggressive muscle breakdown and impaired muscle regeneration. A therapy can therefore be protective, regenerative, or both. An ideal therapy shifts the balance back towards regeneration to parent protection.
One potential path to establishing a functional cure is by assessing quiescent satellite cells, which are the stem cells the body relies upon to repair and regenerate damaged muscles. These critical drivers of muscular muscle repair are emerging as potential significant competitive differentiator by addressing the dystrophin double head problem. We believe we have highly differentiated delivery mechanism, including ability to access quiescent satellite cells, suggesting the potential not only to protect existing muscles from further damage, but to provide basis for regeneration of new healthy muscles. One potential driver of functional benefit that we saw in cohort 1 could be due to our ability to access quiescent satellite cells, a target cell population that transferrin receptor targeted antibody conjugates and other platforms do not reach.
Driving muscle repair and regeneration that manifest as improvements in muscle function before it fully manifests as dystrophin level in a western blot from a muscle biopsy. Now, I'll turn it back to Dipal.
Thank you, Dr. Rajan. We'll now shift gears and take a look at our 2026 inflection points. We have significant clinical momentum and are well-positioned to continue to advance our pipeline through multiple near-term clinical milestones. All 8 study participants in cohort 1 of ELEVATE-44-201 have now progressed to the open label period, where they are receiving 6 doses of ENTR-601-44 at the 6 mgs per kg dose. We expect to see a continued benefit of functional response over time, and we look forward to sharing data from the open label period by the end of this year. Additional study participants are now being dosed in cohort 2, in which they will receive placebo or 3 doses of 12 mgs per kg of ENTR-601-44.
We anticipate we'll see an increase in exon skipping and dystrophin expression in cohort 2 with continued functional benefit. We plan to share data from cohort 2 by the end of this year as well. Our ELEVATE-45-201 study is now fully enrolled with a data readout expected in the middle of 2026. Because the design of cohort 1 is based on previous modeling, we expect plasma exposures to be similar to those seen in ELEVATE-44-201 cohort 1. This implies the potential for lower than expected exon skipping and dystrophin, but the potential for functional improvement at the 5 mgs per kg dose. I'd like to take a moment to emphasize how incredibly grateful we are to those living with Duchenne, their care partners, and the study investigators and personnel who are taking part in our clinical study.
Advancing potential therapies is not possible without the participation of the community, and we're inspired every day by their commitment to make progress for those living with Duchenne. To wrap up today, we have established significant clinical momentum with our top line results from ELEVATE-44 cohort 1. Importantly, we believe that we have achieved a drug treatment response that has pushed the dystrophin levels above a certain threshold required for functional benefit. We continue to remain on track towards multiple near-term value drivers, including our ELEVATE-44 data readouts for the cohort 1 open label period and cohort 2 by the end of the year, and the ELEVATE-45 cohort 1 data readout planned for the middle of 2026.
We are executing well against the goal to have 4 clinical stage programs in our DMD franchise in 2026, and our partners at Vertex are on track to complete enrollment and dosing in that study and share results in the second half of 2026. Beyond neuromuscular, we expanded our pipeline late last year to include ENTR-801, our first IRD clinical candidate targeting Usher syndrome type 2A, and we plan to nominate our second IRD candidate this year. We are confident that our efforts to establish a new class of genetic medicines will unlock new disease targets, all within our proven efficient development framework. With cash runway into the third quarter of 2027, we have the team, the pipeline, and the financing to deliver on our bold mission for both patients and investors alike. With that, we're happy to take your questions.
Our first question comes from Kostas Biliouris from Oppenheimer. Please go ahead.
Thank you for taking our question, and congrats on the update here. Maybe a twofold question from us. Could you share what dystrophin levels does your updated model predict for 12 mg per kg and 18 mg per kg as investors are trying to compare your dystrophin levels with against the competitor Avidity? The second question is there a way you can demonstrate that your clinical benefit or functional benefit is superior to competitors even with lower dystrophin levels? Maybe how physicians will be thinking about that in the commercial setting if you have lower dystrophin levels than competitors, but your functional benefit is superior to others. Any thoughts around that would be helpful. Thank you.
Great. Thanks, Kostas. Appreciate the question. First and foremost, I really do believe that today is an important day as it's a win-win for patients. Not only have we established safety at the 6 mg per kg dose, but as you just called out, we also have, you know, very strong functional benefit at a low dose. That's a big deal because that's what it's really about, safety plus functional benefit. To your direct question, you know, on the dystrophin levels for cohort 2 and cohort 3, what we're essentially doing is we're right shifting everything by 1 cohort. We expect to see double-digit dystrophin levels in cohort 2 and then, you know, a linear or nonlinear increase above that for cohort 3.
We fundamentally and fully believe that based upon this updated modeling on the juvenile NHP model, that we will be very competitive when it comes to dystrophin levels alone as we look towards cohort 2 and certainly cohort 3. To your second question in terms of benefit and how we kind of match up, you know, I think we've already shared a lot of functional benefit today. The time to rise velocity metric is a very rigorous, non-biased, non-noise generated functional measurement. What we've shown today is not only statistically significant, but also clinically meaningful benefits within that 1 TTRV measurement. We do also have good trends within the 10-meter walk as well. You know, these data are early, right?
This is at the day 127, hence our surprise that we already received functional benefits. Those are probably because of some mechanistic differentials between our approach versus other companies as well too. As it stands today, our functional benefit is better than others as well. It's also very clean. We represented the data as the data showed. It was all based upon 6 patients and then, of course, 2 on placebo. Other companies that you had mentioned, you know, look at this from a pooled response. It's kind of very difficult to do an apples to apples comparison between ENTR-601-44 and other companies. What we can say for TTRV, as it stands today, we are in very, very good shape when it comes to functional benefit.
Thank you. Our next question comes from Jonathan Miller from Evercore ISI. Please go ahead.
Hi, guys. Thanks so much for taking my questions. I'd like to start with the AUC, which seems to be driving the delta in dystrophin from what we expected. I'd love to get more color on why you think it didn't translate so neatly from healthy volunteers. It seems like there's a really substantial drop in the realized exposure here that I'm not sure we can say other programs in this space have seen, at least when we think about the doses they've gone forward with in patients versus healthy volunteers. Why would your program here have a bigger difference between healthy volunteers and patients than others have observed?
Maybe secondly, when we think about the functional benefit, can you give us a little bit more granularity on the baseline TTR for both the placebo or treatment arms and maybe the range of changes, the variability in TTRV for the treatment arm? How variable is that on a patient to patient basis?
Great. Thanks, John. I'm gonna ask Natarajan to address the AUC question, and then we'll go to the second question after that.
Thanks, John. One, it is a new modality, so difficult to kind of predict what the adult and the pediatric population will do. Secondly, there's not much data on, you know, the plasma exposures for other platforms. I think it is very difficult to conclude that there were, they had similar exposures between, you know, pediatric population and adult population. I think we do see similar trends in the NHPs. Yeah, you know, from a mechanistic point of view, that kind of makes sense that, you know, we saw lower exposures in pediatric patients, and we saw lower exposures in pediatric juvenile NHP as well.
Okay. The second question, John, was more around TTR. I think it was a two-part question. One was, and correct me if I'm wrong. One was the baseline TTR and what we observed. Second was of the variability around the TTRV as a measurement. I think I'll ask Natarajan to jump in, but, well, why don't you take it first?
I think the TTR velocities, initial velocities are going to vary between patients. We have only 6 patients. What is great about our results is that regardless of where they start, or regardless of the severity of the disease or the age of the disease, we saw trends towards improvement in the TTR velocity after treatment. I think that's probably the most important thing to remember, is that regardless of where they started, they ended up improving the TTR velocity.
I think the variability question between TTR and TTRV is answered by the calculation around TTRV. I think TTR has some bias associated with it, and the calculation to get to TTRV, which is essentially 1 over TTR, takes out a lot of that bias, takes out the outliers, takes out some of the noise that's associated with it. I think that's why most companies, not only us, but other companies as well too, are looking at this as an endpoint today.
Sure. The range of values in TTRV among the six patients in the experimental arm, like how variable is it in your cohort?
Yeah, it is variable. We had, you know, TTRs, you know, across the spectrum.
As would be expected, right? Because the severity of the disease is different amongst the 6 patients that were on treatment. There is variability around what the TTRs look like. Everyone's is gonna be a little bit different from that measurement. What we did see, John, I think the point that we did see was that the results were very consistent, they were clinically meaningful, and they were statistically significant.
All right. Thank you.
Thank you. Our next question comes from Joseph Thome from TD Cowen. Please go ahead.
Hi there. Good morning, thank you for taking my questions. Maybe just one. I guess still trying to understand a little bit in the recently completed juvenile NHP study that you completed, I guess mechanistically why exposures would be lower in juvenile NHPs versus adults, if you can kind of help us with that, and are you anticipating presenting that data going forward? Second, when we look to the 2nd cohort as well, should we also be expecting more than a dose proportional increase in exposure in the satellite cells? I guess that's kind of a way of getting at what do you expect for the functional endpoints in the 2nd cohort? Thank you.
Great. Thanks, Joe. Thanks for those questions. Natarajan, do you want to talk about the juvenile anything?
Yeah. I think we still are understanding the mechanism why the exposures would be low in the juvenile patients. The consistency that we see with the NHP data between the adults and juvenile, you know, explain some of the differences. It could be because of the differences in lean mass, muscle differences between the two populations. In when it comes to what we expect in terms of in terms of cohort 2, we are expecting a linear increase in exposure in cohort 2. Based on the modeling from the juvenile NHP data, I think that should give robust exon skipping and dystrophin. As people mentioned, you know, we have right shifted it.
You know, what we expected from cohort 1 is now probably what we would get in cohort 2 in double digit dystrophin.
To build on that, Joe, just from a functional benefit perspective, our expectation is the functional benefit will continue when we go to the second cohort. That alone would be a big win, the sustainability of that functional benefit over a significant period of time.
Great. Maybe one more, if I can.
Sure
the age of the placebo patients is just a little bit higher than the age of the active arm. I guess, do you think that played in at all to the results here? I guess we can't see the individual ages, so I guess, what should we read into that? Thank you.
Yeah, it's a good question. I think though, the average age in the placebo looks to be high, higher than the treatment, but we have all age groups represented in the treatment group as well.
Just a note on top of that, just recall that all the patients were ambulatory and all were on steroids as well. There was a consistency around that, around those parameters too.
Great. Thank you very much.
Thank you, Joe.
Our next question comes from Paul Choi from Goldman Sachs. Please go ahead.
Thank you. Good morning, and thanks for taking our questions. My first question is with regard to CK, and if you could elaborate a little bit more on that. Specifically, do you think this is the evidence that you've seen to date is more a sign of protection or potential evidence of improvement in the patients given the dystrophin data? If you could help us triangulate that would be great. My second question is with the 45 readout coming up here in the near term as well, can you clarify if, you know, your learnings from your PK and AUC modeling here for the 44 program has implications for 45 and just any changes in assumptions we should make for that program? Thank you.
Thanks, Paul. Natarajan, why don't you answer the first question? I'll take the second, please.
Yeah. Paul, that's a good question. As you know, with this change in dystrophin, modest change in dystrophin, we didn't see statistically significant changes in CK, and that is understandable because we are not probably addressing the muscle fibers issue, but we are addressing the regeneration issue by satellite cells. That's why there is this, you know, this concordant between the functional improvement we see and the dystrophin levels that we see. In terms of your second question on 45, we do expect the exposures to be lower in 45 as well. Again, the bar for 45 is not very high. The, you know, the competitor is 1% or so dystrophin.
I think, you know, from that point of view, 45 is a different beast altogether.
I think that's an important point, especially around the second question, Paul. The numbers are very different. The dystrophin baseline numbers are very different, since, as Natarajan said, that they're lower. We've also been guiding to single digits when it comes to a dystrophin production perspective, and we also, you know, believe that that will still stay intact. We will see how it goes with cohort 1, but I think that's still intact in terms of our expectations. Like what we said with cohort 1 for 44, you know, we have this dose escalation, and that becomes very, very important. It's always been an important part of the Entrada strategy, the ability to go in at a low dose but then escalate beyond that.
We have many shots on goal here, and this is a long game, of course. To your first question, just to go back a little bit, you know, I think that's a, it's a very good question in terms of what is the role of dystrophin. You know, I'd definitely like to ask Dr. Servais to get his viewpoint on this because we feel as though there's a dual role in dystrophin. You know, I'll pause there and maybe Dr. Servais, if you can hear us, maybe you can answer part of Paul Choi's question.
Thank you. Our next question-
No, I have one second, operator. Dr. Servais, can you hear us?
Yeah, sorry, guys. I think we're having a tough time. Dr. Servais is traveling through Europe right now, and he was very generous with his time. Let me ask Dr. Servais one more time. Dr. Servais, if you can hear us, you know, perhaps you can address the question around the dual role of dystrophin and the importance of regeneration, if you can hear us. Okay. We'll pass on that. Paul, to that answer.
Can you hear me?
Oh, go ahead, Dr. Servais.
Yeah.
Yes, you can.
Yeah, sorry. I was on mute. Actually, dystrophin is the shock absorber of the muscle cells, that's for sure, but also it fixes several protein. I wanted to emphasize that, you know, muscle biopsy is just a snapshot at a very specific moment in time.
At a very specific place. If you look at Duchenne muscular dystrophy programs, obviously in very early biopsy that have been performed, the level of dystrophin is actually much lower, right? If you look at the first data from Dyne or from Wave, the very early dystrophin level or dystrophin was also much lower than anticipated. There is really a time sensitive issue here in the questions of the amount of dystrophin that is expressed.
Great. Thank you, Dr. Servais.
Thank you. Our next question comes from Myles Minter from William Blair. Please go ahead.
Thanks for the comprehensive presentation here. I was just wondering whether you could comment on the actual tissue concentration of the 44 skip that you're treating with here. You know, we did have some questions going into the data whether you were going to achieve adequate amounts here with this dose. And then maybe just from your preclinical data, just the idea of the split percentage of where the 44 skip is going to the actual muscle tissue versus the satellite cells, that would be helpful. Thanks very much.
Great. Thanks, Myles. Natarajan?
Yeah. Thank you, Myles. When we looked at the muscle. The muscle biopsy was taken six weeks post the dose, and the Cmax for muscle exposure is less than 24 hours. We did expect low, you know, muscle concentration. We saw single-digit nanomolar at the time of biopsy, on an average. There were outliers on both sides, but on an average, I would say, single-digit nanomolar. The good news is that we do have good exposure, yet, you know, as we would have expected based on plasma exposures, corresponding exposures in the muscles. In terms of your second question, what proportion goes to the myofiber versus satellite cells, I don't think we have done that experiment yet in preclinical studies.
Thank you. Our next question comes from Yannis Saratsis from Cantor. Please go ahead.
Hi, folks. Appreciate the time today. Just a couple questions. I mean, one, I think it's pretty remarkable that the safety was so clean. With that in mind, as you kind of shift things to the right in terms of the dosing to cohorts, is there any opportunity to kind of assess and open the 18 mg per kg cohort in advance to start running some of these in parallel? Secondarily, a lot of the dystrophin skipping and kind of tissue uptake seem to be dependent on kind of clearing or saturating clearance.
Just kind of curious if there's any signals of that early on, if that's, you know, some of the excretion data that you previously reported, if you could use some of those metrics here, to kind of gauge how close you are to that threshold to really start seeing, the exon skipping component, begin to accelerate.
Great. Thanks, Yanni. Natarajan?
Yeah. We have not looked at urinary excretion in the cohort 1. We would add those things as we go to the other cohorts. We don't have excretion data. The general principle is true. I think, you know, as a first pass organ, kidney does receive the first bolt of the oligos. When it gets saturated, you get a lot more to the muscle. Based on the exposures that we have gotten in the plasma, I would say I think that is why we have a good confidence that, you know, the exposure in the muscle should at least linearly increase to get to probably above 50-100 range in the 12 milligrams per kg. That should give very robust exon skipping in dystrophin.
Go-got it. A-and, and from-
Yannis? Yannis, you appear to be back on stage.
Oh, sorry. I thought you guys could hear me. Yeah, just a follow-up to that. With regards to kind of opening up the cohorts in parallel, is there any flexibility to do that to assess kind of safety as the 12 is progressing to then, you know, kind of accelerate things?
Yeah, it's a good question, Yanni. I think it'll be pretty difficult based upon the protocol that we have to be able to run both in parallel. I think one builds off of the other, right? Even our 6 mgs per kg, you know, going to 12 mgs per kg was predicated on what the 6 mgs per kg look like from mostly from a safety perspective. I think that's where for these first in human trials in Europe, that's what they're looking for, and they're gonna look for the same thing when we go to 12 mgs per kg and then, if and when we go to 18 mgs per kg as well. I think it's pretty difficult to find those efficiencies.
The good thing here is that the 12 mgs per kg data is expected before year-end. On top of that, we also expect to have the 6 mgs per kg cohort 1 open label data before year-end as well too. In the next 6, 7 months, we should have clarity on both of those too.
Got it. Understood. Thank you so much.
Thank you, Yannis.
Thank you. Our next question comes from Anže Godec from Guggenheim. Please go ahead.
Hello. Good morning. Thank you for taking our questions. We just have two quick questions.
Around what prompted you to do the juvenile non-human primate study in the first place, and second, going to satellite cells, what are your thoughts is about whether the drug targets the satellite cells preferentially, or it is just that this slow, this little low dystrophin increase is sufficient to kind of, achieve a threshold where you start getting productive asymmetric cell divisions? Thank you.
Perfect. Thank you for that question. Natarajan Sethuraman?
Yeah. The juvenile study is part of the preclinical package that we do, yeah, in terms of long-term studies in juvenile monkeys, to enable, you know, treatment of juvenile population. To the second question, I do believe that there is a threshold level. You know, what is the threshold level for, you know, producing dystrophin level that shows up in a western blot may be very different from the threshold level that is required to activate satellite cells. Some of the preclinical experiments that we have done where we treat animals for three doses and give 12 weeks of washout, we still see majority of the satellite cells to stain for PMO.
It may be, you know, because of the proximity to the blood vessels, et cetera, it may be a physiological thing that satellite cells do get more. We still have to figure that out. We are doing experiments to do that. The results do indicate that we probably have more regeneration than repair at this point.
I think it's a good question. I think also just to provide context, right? You know, we're still learning. We meaning Entrada, but also I would say, other pharmaceutical sponsors, patient groups, KOLs, et cetera. We're still learning about what the role is of dystrophin and how it correlates to functional benefit. To your point about the threshold, that becomes a very important belief. We feel as though we have the preclinical data that shows the ability to get into these, you know, stem cells. I think that's a very unique characteristic. The ability to regenerate quickly may be the driver that's allowing us to get to that threshold that allows us to show functional benefit, albeit at a lower dystrophin level.
At the end of the day, what's really important here is the establishment of safety and of course, the functional benefit for these patients. Dystrophin is important, the role of dystrophin is something that I think is still being informed. Entrada's unique ability to get to the satellite cells is a great effect. More, you know, more analysis will be done by the company to answer some, you know, critical questions. That's the point of a clinical study.
Great. Thank you.
Thank you.
Thank you. Our next question comes from Raghuram Selvaraju from H.C. Wainwright. Please go ahead.
Hi, this is Yan Zhang sitting in for Ram Selvaraju. Thank you for taking my question for this data. My first question relates to ENTR-801. What remaining IND-enabling work and regulatory interactions need to be completed before clinical entry? Could first human dosing be viewed as a possible 2026 then or something that's more likely as a 2027 one?
Great. It's a great question. Thank you. ENTR-801 is our first development candidate that's going into inherited retinal diseases that we're very, very excited about. You know, these programs are still, as you said, they're pre-IND, so I think they just need to continue to go through the normal course of tox studies and whatnot as we prepare, you know, to submit a formal IND. In terms of in terms of timing as to when we will begin that study, we haven't guided to that. We have to get through some of these preclinical analyses. You know, it's likely a 2027, you know, start for that, for that program.
I would also like to point out that we also will be nominating a second development candidate in the second half of this year too. By the end of this year, we'll have 2 candidates with IND soon thereafter within inherited retinal diseases.
Got it. Thank you. Beyond the ENTR-601-45 cohort 1 readout that's expected in mid 2026, what are the gating items for ENTR-601-50 and ENTR-601-51? When do you think we can, when could initial clinical data from those programs realistically follow?
Yeah. Another good question. Right. We purposely staggered our D and D programs to 1 to learn from each other. We learn from 44, we apply that to 45, so forth and so on. For 50 and 51, you know, 50 has approval to move forward in the U.K. What we want to be able to do is we want to be able to learn more about these data that we just generated today from cohort 1 for 44. See what the applications are to the 50 and 51 programs and the 45 program for that matter as well. Decide how best to proceed from a regulatory perspective. We have a lot of different opportunities here.
The satellite cell information and perhaps changing the course of the disease via the entry into the satellite cells puts us into a very unique situation to have, you know, discussions with regulatory agencies about the role of dystrophin and the role of the role of satellite cells. We'll come back, you know, to the community, you know, later on this year with more specificity around how these data positively, and I want to make sure that that word is understood, how these data positively affect the 50 and 51 programs.
Fantastic. If I may, just a quick follow-up.
Sure.
cohort one functional signal in the updated PK modeling, what would determine whether the 12 mg/kg is sufficient to carry forward versus needing cohort three before selecting a registrational dose?
Yeah.
should think about the relevant when regulators. Sorry?
I think it's a good question. I'll start, Natarajan should certainly jump in. I think first and foremost, you know, safety needs to be established again, right? We have that at 6 mgs per kg. There was no renal signals. I mean, safety in this oligonucleotide class of therapeutics alone as a standalone is a big accomplishment in our opinion, looking at a lot of the other approaches that have come and gone over the years. We want to reestablish that, of course, as we dose escalate by 100% and go to 12 mgs per kg. I think that's the first. The second really becomes the maintenance or continuation of functional benefit. We want to be able to see the functional benefit continue at the 12 mgs per kg.
I think that becomes really important as well. I will say the third factor, and it's always been the third factor, is an important one. Once again, it depends upon the relationship between dystrophin and functional benefit. The third becomes how much does dystrophin increase in the second cohort, and what is our belief system as to how that affects functional benefit, right? I think those are the 3 things that we'd be looking for in the second cohort. I think those answers will then determine how we evaluate the 3rd cohort. I'll be a little bit more clear here. If we maintain a strong safety signal, plus we maintain and continue the functional benefit, we may be done.
That may be enough because functional benefit, at the end of the day, plus safety, is what drives the regulatory process when it comes to, when it comes to these types of, these types of drugs.
Fantastic. Thank you for taking my questions.
Thank you. Well, thank you, everyone.
Thank you. That concludes the Q&A session. I will now turn it over to management for closing remarks.
Thank you, everyone. We appreciate you joining us this morning. As you can see, we're very excited about the positive top-line results from cohort 1 and importantly, the clinical path ahead for our DMD franchise, which really has the potential to transform the lives of people living with DMD. We look forward to keeping you updated on our progress and wish you all a great day. Thank you.
This concludes today's conference call. Thank you for participating. You may now disconnect.