Thank you operator, and good day everyone. I'm Sarah Kiely, Vice President of Investor Relations and Corporate Affairs at ProQR. Today, we issued a press release summarizing the top-line results from the phase II/III ILLUMINATE trial of sepofarsen in CEP290-mediated LCA10. The press release can be found on our website at proqr.com.
With me today are Daniel de Boer, our founder and CEO, and Dr. Aniz Girach, our Chief Medical Officer. Following their prepared remarks, Smital Shah, our Chief Business and Financial Officer, will join Daniel and Aniz for a Q&A session.
In order to include your question on today's call, we request that you dial in to the telephone numbers provided in the press release. During the call today, we will make forward-looking statements. There are risks and uncertainties associated with an investment in ProQR, which are described in detail in our SEC filings. I will now hand the call over to Daniel.
Thank you, Sarah, and hello everyone. Today is a sad day for everyone with an interest in our sepofarsen program and especially for all members of the LCA 10 community. Earlier today, we announced top-line results from the phase II/III ILLUMINATE trial of sepofarsen. Unfortunately, in the top-line analysis, the study did not show a difference between the treated and the control arms on the primary endpoint of BCVA or the secondary endpoints.
We are shocked by this unexpected outcome, especially given the remarkable vision improvements that were observed in multiple patients in the earlier trials. To help us understand the root cause, we will conduct further analysis on the ILLUMINATE data in the period to come, and we plan to share these learnings with you later in an appropriate forum.
The results that we will be sharing are hot off the press as we wanted to share these results with you immediately. It will take some time before we will be able to address all the questions that we have on this outcome. Before Aniz will provide his perspective on the top-line results, I first want to thank the individuals who participated in this trial, their families and supporters, and the wider inherited retinal disease community.
I also want to thank the physicians, research coordinators, and the ProQRians who worked tirelessly on the conduct of this trial. Lastly, I want to thank our shareholders who have supported us throughout. While today's results are disappointing, we are committed to continuing our work to develop potentially life-changing medicines for the high unmet need in genetic eye diseases. I will now hand over the call to Aniz to provide his perspective on the top-line results.
Thanks, Daniel. Before we get to the data, I will briefly review the study design to provide some context. The phase II/III pivotal trial for sepofarsen or the ILLUMINATE trial is a multicenter, randomized, double-masked, sham-controlled study. The key inclusion criteria were LCA 10 due to the c.2991+1655A>G mutation in the CEP290 gene.
Participants were at least eight years old and had a best corrected visual acuity or BCVA between 0.4-3.0 logMAR, which is equivalent to 20/50 vision up to hand motion on visual acuity testing. The trial randomized 36 patients across three arms equally. A target registration dose, a lower dose, and a sham arm. The primary endpoint of this trial was mean change from baseline in BCVA at month 12, comparing the active treated arm against the sham procedure.
The top-line results of the phase II/III ILLUMINATE study on BCVA revealed no difference between either of the sepofarsen-treated arms and the sham arm at month 12. Neither was there any difference observed between the pooled doses and the sham group at month 12. In these top-line results at month 12, the mean change from baseline in BCVA in the 160/80-microgram dose group was -0.11 logMAR.
In the 80/40-microgram group, -0.13 logMAR, and in the sham group, -0.12 logMAR. All p-values are non-significant between treated group versus sham with an ANCOVA analysis. Essentially, every group had a one-line improvement. Also, in the notable secondary endpoints of Full-Field Stimulus Test, or FST, and the mobility course, we did not see a difference between the sepofarsen and sham-treated groups here either.
Of note, sepofarsen was observed to be generally well tolerated in the study, just as it was in the phase I/II clinical trial, with cataract, CME, and retinal thinning observed. All in all, no surprises on the safety here, but the big disappointment was the lack of efficacy. Given the limited time for analysis, there are still multiple additional analyses to be conducted, including subgroup analyses.
We plan to present the results of this study at a future medical meeting. Before I turn the call back to Daniel for some additional remarks, I wanted to echo my sincerest thanks to all that have taken part in the study. Daniel.
Thank you, Aniz. While we are disappointed with the results from the ILLUMINATE trial that we shared today, we have confidence in our platform that generated robust data across multiple molecules, mechanisms of action, and indications.
We look forward to continue to advance our pipeline of RNA therapies for genetic eye diseases with two pivotal trials of ultevursen, which was formerly known as QR-421a for Usher syndrome, and behind that, QR-1123 for autosomal dominant retinitis pigmentosa, and QR-504a for our first front of the eye disease program for Fuchs' endothelial corneal dystrophy.
In the coming year, we anticipate sharing data from our Helios extension study of ultevursen, as well as the first data from our QR-504a biomarker study. We are also excited about the potential of our Axiomer RNA editing technology in the eye for our in-house pipeline. In addition, we will selectively partner the technology out in areas outside of CI, like we did in a recent partnership with Lilly that we announced last fall.
ProQR is in a strong financial position, and based on our current spending plan, this provides a cash runway into mid- to late 2024, which provides us with the opportunity to continue to create value across our pipeline and have clinical data readouts in all of our ongoing programs within that runway.
Going forward, I see three priorities for ProQR. First, we will figure out what happens with the sepofarsen ILLUMINATE trial, where we will leave no stone unturned. Second, we will further our commitment to the ophthalmology community with the development of our programs in Usher, retinitis pigmentosa, and Fuchs' endothelial corneal dystrophy.
Lastly, we will continue to invest our proprietary RNA editing platform technology, Axiomer. Before I hand the call over to the operator for questions, I want to thank everyone for joining our call today. I wish we would have better news to share. Operator, we'll now take questions.
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound hash key. Your first question today comes from the line of Yigal Nochomovitz from Citi. Please go ahead. Your line is open.
Great. Thank you very much. Can you hear me?
Here you go.
Hello? Oh, good. Okay. Yeah, sorry about the tough news. That's a real pity. I know you still have a lot to analyze, but I just wonder, you know, did you see any differences in the distribution of logMAR data at the patient level across the three arms? For instance, you know, perhaps more super responders in the drug arm, but offset by those that didn't respond o r were all three distributions of the logMAR data also fairly similar?
Here, Yigal. I'm gonna ask Aniz to answer this question.
Yeah. Hi, Yigal. You know, at this stage, with only less than 48 hours gone, we're just re-looking at the top-line results and therefore, at the mean level, which is the primary endpoint, we can see that actually, all three arms behaved very similarly. We know that there are responders there.
They're likely to be, across the board with all three arms. I think that that's really the bulk of the work as we move into the next few days and weeks as we dive into the individual patient data and also the secondary endpoints to really learn much, much more about, exactly what happened here.
Okay. What's the strategy as far as, you know, taking forward development in LCA 10? Are you leaving open the door for potentially running another study, perhaps a larger study, once you've fully understood what happened in ILLUMINATE o r, you know, are you planning to leave LCA 10 alone and move on to your other programs?
Yeah, Yigal. This data is really hard to suppress. We obviously wanted to share it immediately given the outcome. We are gonna dig deep to understand why this disconnect in the data between the phase I/II and phase II/III occurs, to understand what the root cause is of this. That will help us to inform the decision on the next steps in sepofarsen, where everything is on the table. We can come back to you later once we have done that analysis.
Okay. Thank you.
Thank you, Yigal.
Thank you. Your next question comes from the line of Dae Gon Ha from Stifel. Please go ahead. Your line is open.
Great, good morning. Thanks for taking our questions. Sorry to hear about the data. Maybe just recognizing again, limited information you guys also have with this data. Can you comment on anything to the extent of the inclusion and the baseline BCVA of the participants that came in?
Recognizing, I guess, the understanding right now is baseline visual acuity has more of the meaningful, I guess, prognosticator factor. But anything of the sort that maybe you might have dosed or enrolled more of the, I guess, better BCVA patients at baseline, such that you kind of suppress the effect size, if you will. Just kind of going into what Yigal was just asking. Daniel, you just mentioned everything is still on the table.
I just wanna be clear about this. When you say cash runway is mid- to late 2024, does that scenario also include running another sepofarsen trial, or is that without another sepofarsen trial? Thanks.
Thanks, Dae Gon. I'll take the second question first. There's obviously some spend in that runway on sepofarsen. This is a two-year study. We are now at the 12-month interim analysis, so the study will continue. This does not factor in a completely new trial. Would that be where we land? There's a lot of boxes to check between now and then, and we first are going back to really dig in and understand what happened here. On your first question, I'm gonna defer to Aniz.
Yeah. Thanks, Daniel. Indeed, the logMAR criteria for inclusion into the study was logMAR 0.4, which is equivalent to about 20/50 on the standard acuity chart, and went up to logMAR 3, which is roughly equivalent to hand motion. Now, we know that the majority of the patients that were enrolled in the study were on chart, and therefore they have a logMAR 1 or better.
Importantly, they're evenly distributed across all three groups. I think this is going to be really the crux of the next few hours and days as we go through the data, analyzing this in order to make sure that we get a better sense of the effect distribution and how each patient fared over a period of time.
If I may just ask one more question.
Sure.
Does this data in any way, I guess, raise question marks around maybe, you know, approaching the splice factor approach? I guess I'm just asking broadly on the biological question of, is this more of an antisense oligo approach, or do you think the genetic target itself may be somewhat in question now given the results o r is this more of an operational thing? I know we're kind of at a high level now, but Aniz, what are your thoughts on that?
Yeah, let me comment on that first, Dae Gon Ha. I think we have seen really robust data in the phase I/II in sepofarsen, in the phase I/II in Usher. We've seen consistent data across those studies that was consistent with the non-clinical data as well. We will investigate why the phase II/III trial is so inconsistent with the findings before. That will guide further insights in that.
Obviously, the science behind this is really well understood. There's a lack of approved therapy, so we don't think it has anything to do with the underlying technology and platform. We really need to invest the time to understand what happened here before we can draw any conclusions.
Great. Thanks for taking our questions.
Thanks, Dae Gon Ha.
Thank you. Your next question comes from the line of Jonathan Wolleben from JMP Securities. Please go ahead. Your line is open.
Hey. Thanks for taking the question and unfortunate news this morning. I wonder if you could comment on how the sham group performed compared to your expectations coming in.
Yeah, John. If you look at the sham group, they increased by 0.1 logMAR at the 12-month time point, which is equivalent to one line on the ETDRS chart, which is actually equivalent to what you would expect with the test-retest variability of the ETDRS chart. Really, from our point of view, you know, something like a 0.1 or 1 line improvement is very much in keeping with what you'd expect.
A sham group behaved as it did. I think for us, the most disappointing thing is the efficacy on the efficacy groups themselves. You know, that's what we need to dig into in more detail over the next few hours and days.
Got it. Is there any stratification in the statistical analysis plan?
We didn't stratify it at entry into the trial because of the small numbers involved here. Indeed, of course, our statistical analysis plan goes into an extreme amount of detail of stratification by subgroups. We have to look at that data. We will be analyzing all of these subgroups as time goes on.
Yeah. One more, if I may, on the cash position. I know you had access to two more $30 million tranches over the next 18 months, I believe. Were those tied to any sepofarsen progress, or do you still have access to that capital?
Good question. Those are tied to, by design, to sepofarsen because we were making sure that, you know, planning for success in a hurry for sepofarsen, which we fully believed in with the phase I/II results, that we would have access to that capital as we look at a commercial launch. It was really to fund that. Of course, we won't access those tranches in the absence of that. That's why it doesn't affect the runway really, because the commercial spend also goes away if we are not approved.
Thanks again for taking the questions.
Thanks, John.
Thank you. Your next question comes from the line of Brian Cheng, Cantor Fitzgerald. Please go ahead. Your line is open.
Hey, Daniel. Hey, Aniz. Thanks for taking my call. Sorry to hear about the results. We have known about the variability can be a huge factor, you know, going into this ILLUMINATE trial results. It seems that there is a sweet spot for efficacy, when we look at your earlier study. I just wanna drill on the baseline characteristic a little bit. What's the proportion of patients who were about 2.0 logMAR? Out of the 36 patients, how many of them were enrolled in the U.S. and Western European sites?
Yeah. Thanks, Brian. You know, some of that information we still don't know, I think. Essentially what we had was a reasonably equal distribution across the different sites. Majority of the sites were European, compared to the U.S. In terms of the number of patients that were enrolled per site, again, a fairly even distribution there.
With regards to the baseline characteristics, you know, from the VA point of view, the majority of the patients were on chart. Just to clarify, the on chart patients are those with logMAR 1.6 or better. That was evenly distributed across the different groups as well. I don't know whether that answers your question there, Brian.
Okay. No, I got it. One of the top questions that we have in mind is, you know, how does this data potentially change, you know, your thinking about the rest of the pipeline? You know, you do have multiple programs that are ongoing.
You know, is there a potential chance that you can put more resources to advance some of those other earlier stage programs? Can you remind us what the upcoming data catalysts that are lined up for the remainder of the year? I have one question remaining on the modeling side with Smital.
Yes. I think the data is on the phase I/II trial sepofarsen is so consistent, and we saw a similar picture in our trial ultevursen for Usher syndrome. This year we are expecting a readout in the Helios open-label extension study in the ultevursen program for Usher syndrome. We also have two pivotal studies ongoing, which we will update you on as well.
This year, we also expect the first data from our trial in Fuchs' endothelial corneal dystrophy with the QR-504a program a nd that's also on track. We furthermore have our program for QR-1123 that is entering a repeated dosing study this year. Also, over the course of this year, we plan to advance targets based on Axiomer forward into our pipeline.
As you know, we have a really broad and deep pipeline of molecules for other genetic eye diseases, and we indeed plan to advance later in the year one or more of those molecules forward into development. We will inform people about what those targets are. Yes, we will progress the pipeline over the course of this year.
Okay. Smital, on the modeling side, I know that you've provided guidance on your cash runway, but can you give us a sense on how we should model out your R&D and G&A expenses for the near-term quarter? Thanks.
Yeah. So we don't provide guidance on R&D and G&A expenses or the annual burn. We generally provide guidance on where our runway takes us because there is depending on what stage the trial is in, that does fluctuate, as some. I think the updates as we think about going forward is that, you know, any revenues that we had taken for now are baked in that as we were planning for commercial launch and all of the costs associated with that.
We plan to advance everything else that Daniel just mentioned. Even with all of that, our runway takes us mid- to late 2024, and even in that, we probably have some more flexes. They're not ready to guide to that yet. In that runway, we will basically have data from all of these programs.
Okay. Got it. Thank you. Thanks for taking my call.
Thank you. Your next question comes from the line of Steve Seedhouse, Raymond James. Please go ahead. Your line is open.
Hey, good morning. Thanks for taking my questions. First, I just wanted to ask, in retrospect, what's your best guess at what happened with the super responders in phase I/II?
Hi, Steve. Yeah, that's a good question. We found in phase I/II that the data was consistent in terms of the onset of the effect and the durability throughout different patients. We saw similar responses in the 002 open-label extension study, the INSIGHT open-label extension study. We see good consistency there in the data.
You know, as we previously discussed, there were different response sizes in the phase I/II, and we think they were mostly driven by where patients were in the baseline visual acuity. We saw the more progressed they were towards hand motion, the larger their response was, obviously because they would have less of a ceiling effect. Yeah, that insight didn't change.
Okay. I'm also curious just about the pharmacodynamics here. Do you think you have sufficient, you know, CEP290 correction o r do you think maybe all along you just haven't been achieving that? Related question, do you just given the dosing differences between phase I/II and phase II/III, do you see any differences in vision at earlier time points in ILLUMINATE that sort of go away, or is there just no separation from sham at any point? Thanks for taking my questions.
Yeah, you know, there is no separation from sham at any point, not noticeable. We did test the same dose in the phase I/II trial, 160-microgram loading dose and an 80-microgram maintenance dose. The majority of the patients in the phase I/II and also in INSIGHT were on this dosing regimen.
We have continued this in INSIGHT and then also started treating the second eye on this dosing regimen. From a pharmacodynamic perspective, we feel really comfortable that this is the right dosing regimen, and we have clinical data to support that. Thanks for your question.
Okay. Thank you.
Thank you. As a reminder, if you'd like to ask a question today, please press star and one on your telephone keypad. Once again, star and one if you'd like to ask a question. Your next question comes from Keay Nakae from Chardan. Please go ahead. Your line is open.
Thank you. Daniel, just trying to get your opinion about what you think the read-through is on the platform for your other indications. Obviously, the drugs and the design choices are such because the drugs are designed to work in different ways.
You know, for Ushers, you're looking at exon skipping. For RP, it's more of a traditional GapmeR for Fuchs, as you mentioned, acts at the front of the eye. They do work differently. You know, how should we view a read-through from LCA 10 or sepofarsen to your other programs?
That's a good question, Kay. We expect limited read-through for some of the reasons you mentioned, but also because we saw really consistent results from the non-clinical data into the phase I/II trials across multiple molecules across multiple patients, and then into extension studies.
In our view, the outlier here is the ILLUMINATE result that we are presenting today. Therefore, we remain confident in the platform as such. We are advancing these programs that you just mentioned. They are in the clinic. Within our cash runway, all of those will have readouts, including two of those that have readouts this year. We look forward to reading out those trials.
Okay, thanks.
Thanks, Kay.
Thank you. There are currently no further questions. I will hand the call back to you.
Thank you, everyone, for participating in today's call. As I mentioned earlier, I wish we had better news to share, but unfortunately, that's not the case. Thank you all for participating. Bye.