Okay, we're going to get started in our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have Stephen Romano joining me today, Chief R&D Officer. Welcome, Stephen. Thank you very much.

Nice to be here.

So there are some audience members who may be less familiar with the silent story, so can you kind of walk us through the story, what programs you're working on, milestones over the next few months or next 12 months? Could it also be helpful?

So we're a global clinical stage bio-pharmaceutical company. Our technology is focused on small interfering RNA. Our compounds are 19-mer blunt-ended double-stranded oligonucleotides. Obviously with sRNAs, you target very specifically the gene transcript that you're interested You can silence that transcript. It's a durable effect, but it's reversible. And we have a number of programs in the clinic. I can start with our most important one right now is a tempera 6 compound is targeting tempera 6 for polycythemia vera that is in phase 2 we talk much more about that in a moment we did actually develop LP little a as well so we have an LP little a compounds or lacerin that is a phase 3 ready asset we are looking potentially to partner that that's a large phase 3 program a cardiovascular outcome trial that would be required to execute so that would be something that would you know generally require a partnership so we're very excited about the data we generated but that's essentially ready to move forward when a partner is identified I think a lot of folks are waiting for the for the data to come out from the Novartis Horizon program to kind of put a seal on the confidence in the translation of the benefit into the real-world setting so but that is another compound we have there is a third compound in the clinic that was actually designed by us, and AZ has, but is returning to us, and that's an ANG-PTL-3 compound completed phase one. They're presenting that data actually now and throughout the year, but that will be returning to us. Then we have a number of preclinical programs, and I'll just highlight a couple of those. We have a compound, GPR-146, that is a novel target. It's not yet been validated in the clinic, so very excited about that. It's targeting a non-LDL receptor-dependent reduction in the production and release of very low-density lipid proteins. So we're very excited about the opportunity there. We would look to pursue that in a rarer condition, such as homozygous FH. So very excited about that. And we also have a compound that is targeting inhibiting. And that's a very, as you know, a very sort of exciting area. There's some compounds that have already been translated into the clinic in early phase development a very exciting opportunity potentially at you know obesity and cardiovascular risks and that's something that we would probably choose to do with a larger partner but that's that's our set of activities we're also looking at extrahepatic so there are opportunities beyond the gal neck targeted therapies that we utilize now and that's technology that we have currently and are moving towards and we'll hopefully be able to share some data later in the year around targeting other extrahepatic cell and tissue types.

Great. Thank you. And so PV, we have data, the official guidance is by early August or something like that?

So you mentioned catalysts. So the two main catalysts for us is that there's one external, which is the completion of the Horizon trial, which will give us a sense of where we stand with LP and the potential to continue our partnership discussions. But I think most importantly is the phase two data on polycythemia vera. And that trial has been running very nicely. It's fully enrolled. The last patient, last visit will be by the end of this month, so by July 1st. So we'll have results of that to share with the market by probably the second, third week of August, mid-August.

Got it. And backtrack, big picture, PV, when we think about the market, can you talk a little bit about the nature of the disease? What is mortality like? How is quality of life impacted? What's the Imet need like?

Yeah, so polycythemia vera is a myeloproliferative neoplasm, so these patients have clonal expansion of certain cell lines, RBCs in particular, causes them to have very viscous blood because of high hematocrit, so the volume of hematocrit, excuse me, the volume of red blood cells in their circulation is high. That puts them at risk for thromboembolic events, so cardiovascular death and thromboembolic The patients are typically divided into high risk and low risk. The high risk being older patients, usually over 60, and with a history of thromboembolic event, or anybody with a history of thromboembolic event, falls into that high risk category. And then low risk is the absence of both of those two. Treatment for these patients, this is a chronic condition, and treatment is typically, you know, these typically are actually diagnosed in their fifth and sixth decade. So we're looking at older patients generally, although many patients do now come in as early as late 30s, early 40s, but typically 50s and 60s, but they can have a requirement for management of their disease for the next 15 or 20 years. What you want to do is reduce the risk of cardiovascular issues, as I mentioned, thromboembolic events, bleeding as well, and you do that largely by trying to keep their hematocrit level below 45. So keeping the hematocrit level below 45 has been associated with a benefit in these patients. So there's been a study done, an Italian study back in, and it was, excuse me, it was, it came out in the New England Journal of Medicine in 2013, but it showed that even in comparison to maintaining hematocrit in the range of 46 to 50, those patients who were not well controlled, so were managed in that 46 to 50 range, had a four times, four-fold elevation of cardiovascular death as well as thromboembolic events. So the guidelines really stress maintaining patients below 45. Typically, those patients are managed early on with phlebotomies. They can be anywhere from 250 to 60 mils of blood being removed to reduce the volume of the blood that is represented by the high hematocrit percent, and that helps patients. But that also can contribute to their general iron deficient status. Now if patients aren't controlled early on with simply with phlebotomies with an addition of a low-dose aspirin, they can go on cytoreductive agents as well, and some of the high-risk patients may even begin treatment with cytoreductive agents, and those are hydroxyurea, for instance, which is an older medicine but effective, although it has toxicities associated with Also, a drug, the pegylated interferons are helpful, and then even the JAK compounds, JAKOFI, for instance, and all of that is reserved for second or third-line treatment in patients who are not responding well to hydroxyurea. So there is a range of available treatments, but the fact is there is a need to have a durable suppression of hematocrit, particularly in patients that we refer to as phlebotomy-dependent. And that's the population we studied in phase one and which we're studying in phase two. And those are patients that require a minimum number of phlebotomies, for instance, three, at least three in the previous six months or five in the previous year. That population of patients often requires additional treatment because they don't necessarily tolerate the frequency of phlebotomies required to maintain their hematocrit, so there's some compromise in the management of those patients. So we feel that's an important population to target. What I didn't say is it's an orphan condition, about 150,000 to 170,000 patients in the U.S., probably a similar amount in Europe, and probably about 3.5 million worldwide. So it's an orphan condition, but it's not the rarest of conditions.

You answered almost all my questions. Anyway, so what percentage of those 150,000 patients are treated at the moment with these existing drugs?

Well, the majority, once diagnosed, the majority are treated. So the majority, again, are typically, and particularly if they're on a low risk end, they start with phlebotomies, and then they can add on other therapies as necessary, but it's a majority.

So at the end of the day, as we think about the peak sales opportunity, it's a good sizable chunk of patients, and then how should we think about the price bookends?

Well, I can only say that, look, the premium priced programs, excuse me, the medicines that are out there, for instance, Bezaremi, which is a pegylated interferon, or Jacofi, they are premium priced at over $200,000, you know, the WAC price. So it is a premium price market. This is an orphan condition, so there's not a huge hurdle for access. We have actually done research, talked to HTA folks in Europe, talked to some of the major insurers in the U.S. in preparation for our Phase III design, because obviously with any program, specifically our registration program, it's important to hit the registration endpoints, but the payers often have other things that they're interested in as well. So we get that, we gather that input, and it informs the final design for the Phase Okay. I meant to say, but by the way, they are expecting that this is going to be a premium price product, that there will be relatively low hurdles, because again, it's an orphan condition and the need is there.

So like you mentioned, the end goal here is to keep patients below hematocrit levels below 45. So when we think about your Phase 2 program with your product, what's the take-home message here. What did you see?

So phase two is ongoing. It's almost done. So what I'll do is reflect on the phase one data. Oh, right.

I call it, I can start at phase two, phase one. Okay.

Yeah. So the phase one data that we completed, we showed that we evaluated three different dose cohorts, three, three mix, six mix, and nine mix per kg. Each of those cohorts received four doses, Q6 weeks, so week zero, six, 12, and 18. And then we followed them out to 34 weeks. What we saw was is all the patients, and by the way, in that particular phase one trial, we allowed anybody regardless of their baseline hematocrit to come in. In phase two and three, we restrict that to patients who are well controlled, meaning they enter the trial under 45, because I think it's a fair, you know, sort of baseline setting for all patients. And then you address the benefit of drug versus placebo. But in an open-label phase one, we allowed everybody to come in regardless of their baseline, and we saw a very consistent effect across all patients. And if you looked at the patients who were well-controlled who came in, whether they received 3, 6, or 9 mg per kg, all of them actually maintained their hematocrit below 45 without the need for phlebotomy during the treatment period of the study. So we feel very, very confident that moving into Phase 2, we can look at both the 6 mg, we chose the 6 mg per kg dose to take forward, but we're looking at two intervals, Q6 weeks and Q12 weeks, because the persistence of the effect that we saw in phase one beyond their completion of the four doses all the way out to 34 weeks in many of these patients actually gives us confidence that we could look at a less frequent dose interval, and that's what we're doing in the phase two.

And so to be crystal clear, you chose six as opposed to nine because?

Well, you know, like with any Phase I study, you're looking at a range of doses. We did not see any particular strong dose effect on the clinical measures, the clinical outcomes, which is whether or not you're maintaining hematocrit below 45 or required a phlebotomy. But if you looked closer at some of the biomarkers, like, for instance, the elevation of hepcidin, you saw what looked to be a more robust elevation of hepcidin in the 6 and 9 mg per kg group. group, you didn't see any difference between those two or any meaningful difference between those two higher doses. But it did appear that you had a larger and more robust effect on Epcidin. Even though, I just want to underscore this, even though the 3mg per Kig group, if they were well controlled when they entered the study, also did not require phlebotomies or had excursions of hematocrit above 45. So all those three doses worked, but you see an elevation in Epcidin on the 6 and 9. it made sense to take forward one of those higher doses, and you never really need to go higher than you need to, and there was no clear indication to go from six to nine. So six is a dose.

Yeah, and to be crystal clear, you saw durability maintained for all three doses, too.

For all three doses, generally speaking, because we're looking at averages here across the three cohorts, you see a persistence of effect well beyond their last dose. And in most of those patients, that actually continued out to week 34. So that's a very predictable, consistent, and robust effect. And that, again, gives us confidence to look at a longer drug interval in phase 2.

And so now the phase 2, we're prepared to read up. You're prepared to top line that in August. And so it is now a placebo-controlled study in testing two different dosing intervals. And so what are you expecting on this same similar primary endpoint? What do you want to see?

So, again, in the study, everybody is well-controlled, and it's blinded, and we have a placebo. So it's a two-to-one randomization, as we talked about. I mean, if you look at, I think everybody's going to look at rust-for-tide data because that's the largest study completed in a very similar population, if not the same. And they showed a 77% response on drug versus a 33% response on placebo in about 290 patients. So you're looking at a placebo-adjusted effect of about 44%. So obviously, we'd like to see a robust effect. I can't predict the placebo response in our study. There's just too few studies to make that claim yet. We anticipate it will be somewhere between 20% to 30%. So we're looking for a robust effect over placebo.

And so, like we established there are two dosing arms. For the study to be technically static, can either arm be placebo or must, I don't know, one arm?

So the analysis is really largely going to be based on the pool data set, but we'll have enough data for each of the arms to consider the dose that we want to, I should say, the interval we want to take forward into phase three.

And speaking of bus for tide, how are you exactly differentiated otherwise if the I should say, if you did show the same efficacy, how else are you differentiating that?

Well, clearly as an siRNA, we have a durable effect. So they are giving a memetic. So essentially they're giving a synthetic exogenously administered hormone. That has to be given frequently. So typically for their product, it's a weekly injection. So obviously we'd like to make it more convenient, reduce that frequency to at least Q6 weeks and perhaps as infrequent as Q12 weeks, you know, it's just a different mechanism. We want to be able to demonstrate a very robust, durable effect that both patient and physician can be confident, can be achieved between intervals. And the thing with epcytomimetic, obviously, if you skip a dose, you may have some rebound, and that might be a concern in the real world when you translate effect into, you know, sort of effectiveness. this, but the bottom line is we want to show, demonstrate a robust and predictable, consistent effect between a lengthy period, a reasonably lengthy interval between injections.

And so again, from the phase two, it was basically every patient's 100% response rate on the efficacy.

Dr. In the subgroup of patients, about half, who were well-controlled when they Because remember, in the phase one, we allowed patients, in fact, we had patients at hematocrit levels of up to 59. And even in those higher hematocrit levels, we saw a very nice improvement. Obviously, they're starting from a higher dose, but you're seeing them come down nicely. In the well-controlled population, you generally see them maintain their... And that is your current phase 2 population. And that is the population. Yes.

And so, I think it was, was it 10 patients worth within that subgroup? So how, can you share like what, how many patients were in the 6-mig group compared compared to three and nine, actually, in that out of 10?

Dr. We had 20. I'd have to go back and look. I don't want to throw out the numbers. Dr. But they're small numbers across each of the arms. But the bottom line is that's why, you know, I can say very clearly that either three, six, or nine was effective on the clinical measures of outcome, which is the maintenance of hematocrit below 45 without the need for phlebotomy. When you look at the data on some of the biomarkers, like hypcidin, obviously there was a differential effect.

And then in bigger picture, how does the other treatments like Jackify and so forth, what do they exactly show on controlling for a hematocrit?

Well, you know, Jackify has a different usage. So it's for patients who are not tolerant of hydroxyurea or cannot, you know, or just need something. They're not responding well to hydroxyurea. So it's reserved really as a second line. therapy in those patients and you know you can look at their label they did a very nice job of demonstrating the effect in that population I think the response rate was somewhere in the 25% range but you know again as a second line therapy and very very few patients in their placebo arm responded so you know clearly Jacofi has a role in those patients we're looking at a broader population of patients as is Rusfortide so we looked at a population of patients regardless of their standard of care that they're currently on regardless of whether there were low or high risk patients at baseline when they entered. And you know, as long as they were stabilized on their standard of care, we allowed them to come into the study. So you know, we're looking at a broader group of patients, all of whom are phlebotomy dependent, as I mentioned. But that's a much broader population than the Jacofi targeted population.

And so ultimately, should you be approved, Russ Fortide approved, where do you think you're going to be positioned in terms of line of therapy?

Well, I think, again, you know, if you look at the population we're treating and the label we hope to achieve based on what our design of our Phase III program will be, you would say for patients who are phlebotomy-dependent, regardless of risk profile or standard of care, they're the patients that we would go after. So it's a relatively broad population, but of phlebotomy-dependent patients.

And then, so Phase II, let's just say it was competitive. 70% or so on an absolute basis, to be clear. How should we feel about phase two to phase three translation? Have you kind of...

Well, you know, we have, even looking at phase one, the result, the effect of this mechanism is very consistent. So for instance, I have, I'm pretty confident we'll repeat the data we showed in the Q6 weeks, for instance, for this, no question about it. And I think we have a good likelihood, or a reasonable probability of demonstrating the longer interval is successful. So then it's just a matter of moving forward and confirming that dose and interval in a much larger study, placebo-controlled, which is the requirement of the agency. We have orphan designation. We have fast-track designation, but our anticipation is we're going to have to do a confirmatory The other companies have done trials in the range of 250 to 300 patients. I think I can suggest that the effect size of the drug on the primary measure outcome program is such that it wouldn't require such a large study. But in a small population, you still need to have a minimum safety database, and I think capturing symptom improvement is going to be very important as well. The respiratory did a nice job doing that. So we would likely make sure we were reasonably powered, obviously, for those important secondary outcome measures. But until I see the results from the phase two, I can't really kind of sort of clarify But the bottom line, we want to have as efficient a phase three program as we can. We're a first-in-class sRNA. We want to minimize the time lag between the ionis compound that's being developed, you know, and ours. And we've done such a good job executing on our phase two trial, we were able to do that very quickly. And if I just look at the rate of completion of some of the other trials that were done before us, I feel like we can do an excellent job executing even with a larger study.

Great. And so come August, you top-line the data. What kind of details can we expect at efficacy kinetics, or is it just kind of a more simple top-line?

Yeah, as is typical of top-line results, you really want to preserve your details for your research presentation. So bottom line is we would certainly have the primary outcome measure, which is the response. I'm anticipating that we would look at the response or provide the response, which is the number of percent of patients that maintain hematocrit control without the need for phlebotomy. And obviously we also do some safety evaluation. But we may preserve some of the details, of course, for a full research presentation.

And that includes symptom improvement as well, or not necessarily?

So we have to decide what we want to do. That's a secondary outcome measure here, but clearly we would present that in time. So whether that comes into the top line results or not. Remember, this is not a confirmatory phase three trial, but so we want to just stick to the top line on the key efficacy and safety parameters.

And so what kind of special AEs are you kind of caring about?

Well, we don't have any real special AEs. I mean, obviously, our drug has been very well tolerated. Our technology has been really well tolerated, so it's not just this compound. We've got two other compounds in the clinic off of our technology platform. They've all appeared to be very safe and well tolerated, so there's no real issues here. But obviously you always think about events that are significant to that certain population for instance You're suppressing hematocrit here. So obviously you want to make sure you're not overdoing that and overshooting We haven't seen that in our in our programs, but obviously that's something you're going to look at We had relatively low rates of those concerns and then it is an injectable So we're giving it you know subcutaneously you want to look at your ISRs That's more of a tolerance issue in our case, but it's a very well tolerated very few ISRs that were more than, you know, grade one, and all self-limiting.

And then back in phase one, you did not see any grade three events? Pretty good. And so far, or you expect?

It's blinded. I can tell you, though, it's blinded. We look at the safety on a regular basis, but the data are blinded, and I can tell you that it appears to be as safe and well-tolerated as it was in the phase one. Now, keep in mind also we've given this drug to patients with beta thalassemia. We've done a healthy volunteer study. So we're very comfortable with the profile that's emerged.

I see. And as we talk about, like, drug versus placebo behavior, why would a placebo patient have a response fundamentally?

You know, why would they be a positive response? Well, you know, the bottom line is the effect of the disease varies, right? I should say the disease activity varies, but you're minimizing that concern by making sure you have a history of a required minimum rate of phlebotomies in the previous six months. So as long as you identify that, you wouldn't expect them, if you're following them long enough, particularly during the period when you're going to observe a response, you wouldn't expect patients who required more than three phlebotomies in the previous six months to all of a sudden be able to go 36 weeks without one. So, I mean, you just manage that by extending the period of time. Remember, in this 36-week trial, the phase two, we will take patients up to week 18 to sort of, you know, on drug just to make sure that they're acclimated to the drug and treatment, give the opportunity for a full benefit from the active arms of the study, and then evaluate response between weeks 18 and 36. So it would be unusual for someone who required multiple phlebotomies in the previous six once per year to go so long without one, and all they need to do is have one in order to be a non-responder, right? So that's how you manage that.

So your assumption or presumption where a placebo of 23 percent is pretty conservative, you would say that?

Look, I think that's what we can go on based on, you know, what we've, what we know from the literature and what we saw with Ruspertide. So that range is reasonable. We're certainly powered with the opportunity to benefit, to show, you know, a robust effect size over that range. Okay. And hope to see that.

And then should this be positive? I'm very hopeful it's positive. Then you meet with the FDA, and so what's the timeline there before you start phase So naturally we'll have an end of phase two meeting.

We're already preparing for that because, you know, fortunately we have other products ahead of us that have gone through, you know, the evaluations and moved into phase three, so there's a precedented regulatory pathway. we've pretty much you know determined that our trial will be similar to the ones that are being conducted and so that seems like a relatively easy path to clarify but we have to go to that meeting the end of phase two meeting determine the you know the minimum safety requirements and we'll do that I assume we'll have that end of phase two meeting by the end of the year early in January early in the new year and start the study in the second half of the year It usually takes six to nine months to start a large, you know, multi-regional program. But as I mentioned, we feel very confident that we can execute pretty rapidly. But we look to starting the study in the second, in the back half of next year.

Yes, efficiency is what you said earlier. So, like, I think respiratory type phase three, did it take three to four years?

I think roughly.

And so you think you can shorten that?

All I'm saying is we're going to do our best job. I mean, we have, and by the way, until we determine the number of patients, obviously that is going to be important because even if you can trim 50 patients off of a 250-patient study, that helps with regards to kind of timing for completion of enrollment. Right, right. But we have used, even in Phase 1 and Phase 2, sites in four different continents, and we expanded our footprint between Phase 1 and Phase 2. We'll do the same going into Phase 3. I say this because we already have established KOL relationships, you know, links with a number of different investigators in each of these areas. And we'll just expand on that as we did from one to two. Great.

And so meanwhile, I believe you're also working on some formulations. Can you maybe talk about that?

Well, what we're looking to do is right now we're doing weight-based dosing. So we did weight-based dosing in phase one and phase two. We want to move into phase three with flat dosing. And we've done some PKPD modeling that we're sharing with the FDA. We'll update that with the data from the Phase 2, but it seems like we've got a relatively clear path to doing that. We may increase the concentration as well to reduce the number of injections so that no one requires more than two injections as we approach Phase 3 and beyond.

And ultimately, should this also, again, be approved as a sub-Q, can a patient handle this by themselves at home?

Yeah, that's a good point. So what we're planning on is having optionality at the time of launch. So what we want to do, and we've already initiated the development of a pre-filled syringe, and we'll do it in such a way that it can be adapted to either the office or home. We'll determine that based on the work we do in preparation for commercialization.

I see, and that will, that work is happening in parallel as you do the phase three.

That's exactly right. Actually, it started now, so we will do all of that in parallel. We'll still use a violin syringe in phase three, but with the new concentration.

And so I guess it is, my next question is a subject of your FDA discussion. I'm just curious what other kind of major peripheral studies you think you need to do?

Well, you need to do your typical, you know, requirements for CARC, et cetera. That's pretty straightforward, but besides a single confirmatory trial, along with a supportive phase two, which we assume our phase two study will be, that's really what's required.

And then maybe last minute, LP little a, we're waiting for a horizon.

I don't want to say when I think the date, I hear certain things, but I think- Second half of the year, anywhere from mid-year to the second half of the year, so we're looking forward to that. But I think, you know, everybody is waiting to see that, you know, the effect on lowering, robust lowering of LP translates into improved cardiovascular outcomes. So I think that's an exciting point for the field. And I think for us, that will obviously kind of hopefully turbocharge discussions with potential partners. We have a very well-designed phase three program that we've already sort of got an agreement with the agencies on, FDA got very good feedback. so looking to distinguish ourselves from the data that are being generated currently in the studies ongoing so I think we're just waiting for that page to turn before we can come increase those activity around partnership okay and then well over time we'll learn more about your other remaining programs absolutely yes very excited to talk about those in the future okay well I think that's all the time we have thank you Steven thanks very much for walking us through and best of luck on your data.

Thank you very much.