All right. Well, good afternoon. Welcome back from lunch, everyone. We've got Entrada, we've got Nathan and Natarajan here. Unfortunately, Dipal not joining us today, but we've got, I think we've got the core of the talent on the management team with us. So we'll have a, hopefully, a very productive discussion this afternoon. Thanks for joining us.
Thank you very much for having us. Thank you to you for having us and for being so supportive over the last couple of years with the company. Thank you to the whole Evercore team, really. This is a great event, and we're really pleased to be here.
Fabulous. Well, let's jump right in. We'll start, obviously, with DMD, with 44. First things first, there's a clinical hold. Everybody expects to come off. Where are you in communication with the FDA on that? Are you still expecting to come off prior to the initiation of the phase 2s? And when should we be expecting to hear about that?
Yeah, so that's a great question. So, as you know, we ran the Healthy Normal Volunteer trial in the United Kingdom that read out early this summer. The data was fantastic. It exceeded our expectations. And so, while we can't comment directly on specific regulatory interactions we're having, our plan, effectively, at this point, is to take the clinical data package that we have, the non-clinical data that you would expect, you would need to initiate a phase 2 study, combine that, and file with regulators around the world. And we've provided guidance that we would be doing that in the fourth quarter for ENTR-601-44, our Exon 44 skipping molecule, as well as ENTR-601-45, both of which will be going to MAD phase 2b studies, which we hope will ultimately be sufficient to gather accelerated approval. And that's all on track.
So, effectively, in our mind, that's how the hold will clear. The program never really stopped. It wasn't really affected by the FDA hold in any way, shape, or form. And so we're now just moving from the Healthy Normal Volunteer into the patient studies.
Now, there was no hold ex-U.S., and obviously, that's where you ran the Healthy Volunteer study. So should we expect to see those phase 2s for both 44 and 45 to get started first ex-U.S. and then followed by a U.S. start?
Yeah, as you know, each one of the jurisdictions has their own timeline in terms of how long they take to process an application. Our goal will be to get sites up as quickly as we can, regardless of where those jurisdictions are. So if that starts ex-U.S., great, and so that's basically our perspective. We just, we want to get drug to patient as quickly as possible.
And those submissions, you've guided for Q, but we're expecting trial start probably to come into next year.
Correct.
Makes sense. Okay. The one other thing that I want to make sure we talk about is Sarepta's discontinuation of the whole PPMO program over there for safety issues, presumably being caused by their cell-penetrating peptide. Now, you have said repeatedly you haven't seen any hypomag, you haven't seen hypercal. You've been very upfront about that. But given the putative cause of the safety signals Sarepta seeing being the cell-penetrating peptide, Natarajan, how confident are you, and how confident can you be that your CPPs aren't going to drive any sort of renal toxicity whatsoever?
Yeah, yeah, thank you. I think when we look at our phase 1 data in Healthy Normal Volunteers, at 6 milligrams per kg, we not only did not see any kidney parameters moving like BUN, CK, et cetera, but we didn't even see any biomarkers for proximal tubule damage, which is great. At the same time, we are seeing target engagement in terms of exon skipping. Why would peptides be different? You know, structurally, they are very different, right? It's linear peptide versus cyclic peptide. What we are seeing is that when we compare non-human primate versus human, our exposure in the plasma and the muscle is two to three times more than what we see in non-human primate. At the same time, the excretion of the oligo is about 10 times more in the humans compared to non-human primate.
Higher exposure and also dramatically higher excretion.
Dramatic excretion. And the reason the proximal tubules are damaged because of oligos is because of retransportation from urine back into the proximal tubule where they accumulate. So if you excrete more, then that should be less. So all the indications are from our phase 1 clinical trial that we are much cleaner.
Now, part of that reabsorption is driven by the polycationic nature of many of these CPPs. But even the cyclic EEVs, those are still polycationic.
What we are finding is that when the peptide itself is more stable in human plasma compared to non-human primate. We are getting larger exposure into the muscle. At the same time, once it gets into a tissue, it is very rapidly degraded. When you are excreting out, you are predominantly excreting out oligonucleotide without positive charge. That has lesser chance of getting retransported.
Okay, that makes sense. Interesting. Now, your Sarepta's cell-penetrating programs, all their PPMOs were based on the same CPP that they were using. You've explored a variety of different EEVs. The current DMD programs, the DM1 program that's now with Vertex, are they using different EEV vehicles, or are they using the same construct?
For all our neuromuscular programs, we have selected one EEV. The reason for selecting that is that when we look at distribution into the muscle, this has the highest distribution among the peptides that we looked at. And that also creates efficiencies for us. For example, when we compare the TK profile of the compounds, three compounds that we have taken to tox studies, they are almost identical profile in terms of plasma exposure, muscle exposure, urinary excretion, et cetera. So that gives us confidence each program builds on the other when we use the same peptide.
Okay. Yeah, no, that makes sense. All right, so let's talk a little bit more detail on that Healthy Volunteer data that you mentioned. So you've got a mean exon skipping of 0.44%. That was the headline number. And it does seem lower than competitors like Avidity and Sarepta who are pushing 1% or even higher from their reported numbers. So can you contextualize those numbers for us? I think to someone who's not steeped in the DMD space, that feels like a very low number in aggregate. What bars should we be focused on from exon skipping and Healthy Volunteer to drive translation to patients?
Yeah. So the way we look at the Healthy Normal Volunteer study is exactly the parameters that I talked about. How does the PK parameters, distribution parameters, excretion parameters compare from non-human primate to human? So our muscle biopsy was taken at a time which was ideal to look at muscle concentration, not necessarily exon skipping. So we know that from our animal studies, seven to 10 days is where we get peak of exon skipping. But ours is 72 hours post-injection that we took our muscle sample.
Avidity at day 29.
Yeah. So there is a huge difference there. And secondly, the reason we are not attaching too much importance to exon skipping in healthies is that in healthies, as you know, we are destroying the reading frame. And when we do that, those mRNAs get degraded rapidly. Whereas in patients, the opposite is true. When we restore the reading frame, these mRNAs last for a long time. So it is very difficult to compare between what happens in a Healthy Normal Volunteer in terms of exon skipping compared to a patient. But we can compare the PK parameters, et cetera, where you'll get a good idea. And that's one of the main differences. The second thing is that when we look at the normal myofiber versus a patient-derived myofiber, when we compare the exon skipping, it is 20 to 40-fold more in patients, patient-derived myofiber compared to normal.
When we look at single dose versus three doses, the dystrophin production is greatly enhanced in animal models when we do multiple doses. Essentially, the phase one trial is good to look at PK parameters, safety, but not particularly good model to look at exon skipping.
Okay. All right, sure. The safety profile that you just mentioned, very supportive so far. Obviously, we talked a little bit about renal tox, but even beyond that, it seemed like you were very well tolerated in the Healthy Volunteer study. And given that, you've suggested you could continue to explore even higher doses. So where are you in that process? Do you have Healthy Volunteers running currently at 12 mg or, excuse me, can you generate that data in patients instead? Where are we in that?
Yeah, strategically, the goal at this point is to move straight into patients. The ENTR-601-44-101 trial that we ran in the U.K., the highest dose we tested was the six mg/kg. That's going to be part of the regulatory package that we're submitting. For us, it didn't really make sense. We got the information we needed to get from that trial, and it didn't make any sense anymore to continue to dose up. We weren't going to learn anything more. We wanted to move as fast as possible to patients. We'll be exploring higher doses. Based on the clinical package, as well as some of the non-clinical data that we've put together, we're hopeful that we actually should have a relatively high starting dose as we move into the patient trials.
And then from there, our non-clinical data suggests we should be able to dose up two, three, perhaps even four-fold from there. So that's where we'll explore those doses.
In the patient MAD trials.
In the patient MAD trials, exactly.
One thing that you didn't report in healthy volunteers in the public deck was a full dose-response on exon skipping. And Natarajan, I know you said it's not the best place to look at exon skipping, but you see clear dose-dependent muscle exposure increases. Can you confirm at least that as flawed as the comp is, you do see dose dependency in exon skipping as well?
We do. In fact, at 3 milligrams per kg, we did not see exon skipping beyond what we see in placebo. So it was just background. Whereas in 6 milligrams per kg, very significant increase above the background. So there is a dose-dependent increase in exon skipping, even in that flawed model.
Sort of suggests that it's non-linear as well. Is that fair?
Yeah, exactly. Exactly. I think we would probably, you know, if we were to model from non-human primate, right now, 6 milligrams per kg in terms of muscle concentration is about equivalent to 15 milligrams to 20 milligrams per kg in non-human primate. What we see in non-human primate is that till about 20 milligrams per kg, you see a linear response both in muscle concentration and exon skipping. Once you go by that, then it is exponential increase. And that's because of the fact that when you get above 50 nanograms per gram of tissue, then you have a lot more oligos to continuously skip for a long period of time. And then, of course, in patients, you have the mRNA accumulating because of that.
There is a threshold.
Threshold, yeah.
That you have to hit. Okay, makes sense. One thing we discussed very briefly in the Healthy Volunteer comparison to Avidity is the time post-dose that you took your biopsy. Obviously, Natarajan, you said you're doing that to see peak muscle exposure as opposed to exon skipping. But when we go into patients, when do you plan to take your reads and when are you going to be looking and why do you pick those dates?
So we haven't guided as to our timing of muscle biopsy. But when we look at the field in general, the focus is more on dystrophin than exon skipping.
Certainly.
So when we look at dystrophin, first, you need to get the mRNA level up. And interestingly, dystrophin mRNA is very, very low expressed as such. And when you don't have any dystrophin produced, as in the case of patients, then it is even further deregulated. So you need to get the mRNA level up and then make dystrophin. And because it is one of the largest proteins in the human proteome, it takes a while to make it. So that's why you would see people taking biopsy more than a month. So I think generally that's the rule that we would follow also, but we haven't particularly given an exact timing.
You haven't given an exact timing, but fair to say that you would pick biopsy timing in line with the field?
In line with the field and in line with dystrophin expression pattern.
Rather than just an exon skipping read. Makes sense. All right, let's return to the cadence of data coming out of this phase 2. So the 44 and 45 exons with INDs coming this year, you've talked about exon 50 getting started next year as well. So by the end of next year, we're thinking about three patient MAD phase 2s ongoing. Can you give us a rough sense for cadence of those three trials relative to each other and maybe when the earliest we could expect to see some initial patient data out of that?
Yeah, I mean, the next 18 months are going to be huge for us, right? By the end of next year, if you count the VX-670 program, we'll actually have four EEV programs in the clinic in a phase two trial, which is remarkable and kind of transformational for the company. Suffice it to say, based on where we are today with 44 and 45, barring a little bit of uncertainty, those should be right on top of each other. And then 50 will come shortly thereafter in 2025 in terms of getting that started up. In terms of the data readout itself, we're going to hold off guiding as to exactly when that's going to happen because what we want is to hear from the different regulatory bodies to make sure that we've got a coordinated protocol around the globe.
And so what our expectation and what our plan is once we gather that information, then we'll be able to come forward to the investment community and talk a little bit more in detail about what the final trial design looks like. And then ultimately, that will guide when you can expect to see data.
Okay. Maybe then, a little more abstractly, is there a number of patients that you'd want to have in hand before you release data on any particular exon?
Yeah, I think that's right.
What's the number of patients?
I think more to come on that one.
Okay.
I think more to come on that one.
All right. All right, fine. Let's talk a little bit about DM1 while we've got a few minutes here. Obviously, the program in Vertex's hands, but it is, as you say, an EEV program. Presumably, you can learn a lot about the delivery mechanics of the platform from that as well. Can you give us a sense for what you would expect to be public versus what sort of learnings you could take from that program internally that we might see reflected in your own programs going forward?
Yeah, I think in terms of translation across the programs, obviously, these are two very different diseases. The mechanism of action is quite different, but the EEV is the same. And I think one thing that we've been excited about is the fact that not only do we have good safety and PK data from our 60144 program, but obviously, they've come out and publicly announced that they're accelerating their program, the Phase 1/2 . They completed the SAD portion of that 1/2 study, and they've initiated the MAD portion of that 1/2 study. And to us, that suggests that what you're seeing is very good safety across the board, if nothing else, in humans, regardless of mechanism, regardless of construct. So there's some really nice read through there.
And I think when we've looked at it, and you should speak to this, when we've looked at some of the preclinical work in our own hands as well, the EEV seems to provide a very consistent profile across programs when it comes to biodistribution, PK, et cetera. And so I think that's.
Regardless of cargo?
Regardless of cargo. And so.
Although in this case, both sets of cargoes are oligo cargoes.
They are oligo cargoes. That's true. But again, very different mechanism, right?
But the PK and distribution are determined by EEV, not the cargo.
Not by the cargo.
So with the result, you can just put those lines up on top of each other. So all the three programs, the TK profiles and the tox studies are identical.
So as we think forward in terms of our next programs, it's made it much more efficient in terms of actually planning out the trial designs, non-clinical work, thinking about where we would start in the clinic, et cetera. And so that's been quite helpful.
Okay, makes sense. One more on the DMD phase 2s. Obviously, Natarajan, we've spoken often about how different exons have different skipping efficiencies and may have different needs. But when we look forward to data releases, would you expect there to be different dosing requirements in these different exons and therefore maybe different cadence of data releasing in different exons driven by differences in skipping?
Theoretically possible. So we know for a fact that 44 is easier to skip, say, compared to a 51 product. So it is theoretically possible that you would need much higher doses for 51 than you do for 44. And yeah, I think as the clinical programs develop, we'll have a better idea on that. But it is not for lack of distribution, though we see pretty much the same distribution into muscles, whether we use one oligo versus another. But it may take more oligos to skip, say, something like 51 compared to.
When you say there's much harder to skip or much less hard, can you give us an order of magnitude on that? Are we talking about a couple of fold or are we talking about 10 fold or higher where you might be?
I don't think it's going to be 10-fold.
It's not 10.
It's not going to be 10.
It's more modest.
Yeah. It is just the fact that with the 44, there is inherent skipping of 44 in a, say, 45 deletion patient. So with the result, the mRNA levels are a little bit higher. So you're starting from a higher ground for 44 compared to 51 where there is no expression and then hence the mRNA levels are lower. So it's more biology driven than anything else.
Makes sense. All right, in our last few seconds here, you've got it to runway into 2027, presumably covering all three of the DMD phase 2s through some meaningful data. But does that also contemplate getting a potentially registrational trial started? And what are your current thoughts about BD or fundraising around the switch into a potentially registrational trial?
So yeah, from a context setting perspective, the way we're thinking about designing these is it'll be a MAD phase 2b seamless design. So as soon as we go into a clinic, the way we're thinking about it is this is an accelerated approval trial as we go. But you're right. Obviously, we're in the fortunate position to have cash into 2027. And so that should allow for some fairly meaningful readouts before we have to contemplate doing any sort of fundraising.
Thinking outside of DMD, obviously you did your deal with Vertex, very nice for you. Are you considering other sorts of BD deals, whether discovery deals or specific targets with other strategics to add to that portfolio?
Yeah, I mean, we're constantly talking to people just like everybody else in biotech. I'll be a broken record on this one. If somebody comes to the table with an idea that we think makes sense and that allows us to move the platform forward more rapidly or more effectively globally and expand the therapeutic applications, then we're absolutely willing to listen. We try to be quite disciplined about it, though, because it does, even if your partner is doing the bulk of the work, there's still a lot of work and decision making that rolls up through all the same people who are focused on the preclinical work and the clinical work associated with our lead program. So we're thoughtful about it before we actually pull the trigger.
But cargo agnostic, mechanism agnostic?
To the extent it makes sense from the perspective of biology, and we have a control.