Good morning, and welcome to our call today. We will be reviewing top-line data from our phase II AURORA trial of bitopertin in patients with EPP. Before we get going, I want to remind people that we'll be making forward-looking statements on this call, and these should be reviewed in light of materials that we have filed with the SEC and posted to our website. Additionally, please note that bitopertin is an investigational agent that is not approved for use as therapy in any jurisdiction worldwide. I'll begin with an introduction and summary of the data. As a reminder, the phase II development program in EPP includes two trials: the BEACON trial, which is an open-label study being conducted in Australia, and we've presented interim data from that study at EHA and ASH in 2023. Today, we'll be focusing on the AURORA trial.
This is a placebo-controlled study being conducted with 75 subjects in the U.S., with dose groups of 20 mg and 60 mg once-daily doses. This is the first unblinding of data from the AURORA study. Now, in top-line data presentations, I prefer to move directly to the data with minimal preamble, so let's dive right in. On this next slide, we have the key takeaways. We met our primary endpoint, demonstrating dose-dependent and statistically significant reductions in protoporphyrin IX, or PPIX, as compared to placebo in both dose groups. This demonstrates that bitopertin is achieving its intended mechanistic effect in patients, with meaningful reductions in the toxic metabolite that drives this disease. Now, when we look at measures of light tolerance, including our secondary endpoint of cumulative time in light, we did see large improvements in bitopertin-treated patients, similar to what we observed in our open-label BEACON study.
However, these results did not achieve statistical significance because there was a strong performance in the placebo group. While there was a numerical difference with bitopertin treatment; overall, these data on light tolerance call into question the scientific utility of this endpoint, and we'll discuss this more later in the call today. We designed this trial and the BEACON trial to assess the treatment effect from many different angles. If we look at other pre-specified endpoints, there were dose-dependent reductions in the rate of phototoxic reactions with pain and improvements in quality of life, as measured by the PGIC instrument. On both of these endpoints, statistical significance was achieved in the 60 mg dose group. These are endpoints that measure clinically meaningful aspects of the disease for EPP patients. Obviously, pain and quality of life are both quite important here. Finally, bitopertin was well-tolerated with stable hemoglobin levels, and safety was generally equivalent to what was observed in the Roche safety database and our prior experience in the BEACON trial. So those are the summary points. With that, I'll hand it over to our Chief Medical Officer, Will Savage, to provide a more detailed review of the data.
Thank you, John. AURORA is a randomized, double-blind, placebo-controlled trial of two doses of bitopertin in EPP. We compare 20 mgs and 60 mgs of bitopertin to placebo over a 17-week double-blind period. The primary endpoint is % change in PPIX , the disease-causing metabolite in EPP. The key secondary endpoint is the total time in sunlight on days without pain. Other endpoints include additional measurements of light tolerance, pain reactions, and quality-of-life measures. We are presenting top-line results only today. Full results are not yet available. 75 patients enrolled in the study, and we had 3 discontinuations. Baseline demographics were comparable across treatment groups in terms of baseline time to prodrome, geography, and seasonality of enrollment. Baseline PPIX was slightly higher in the 60 mg dose group.
The primary endpoint was achieved with a 21% reduction in PPIX in the 20 mg group, and a 40% reduction in the 60 mg group, as compared to an 8% increase in the placebo group. The differences between bitopertin dose groups and placebo are highly statistically significant. On the key secondary endpoint, total time in sunlight, the bitopertin treatment effect was similar to what was observed in the BEACON study, but was not dose dependent. The improvement of both dose groups over placebo was not statistically significant due to the surprisingly strong performance of the placebo arm. Sensitivity analyses evaluating the effect of baseline light tolerance, baseline protoporphyrin IX level, seasonality of enrollment, and geographic location show similar relationships of active arms versus placebo. Other measures of light tolerance show large improvements in all treatment groups.
Shown is the average time to prodrome, as measured by weekly sunlight challenges. While there are improvements in both bitopertin groups soon after the initiation of treatment, there's a similar improvement in the placebo group as well. Phototoxic reactions are the hallmark and most debilitating pain aspect of EPP. We observed a dose-dependent decrease in the rate of phototoxic reactions that was statistically significant at the 60 mg dose level, with a 60% reduction at 20 mgs and a 75% reduction at 60 mgs. We did see a similar effect in the BEACON study, with an approximately 90% reduction in phototoxic reactions.
The proportion of participants experiencing a phototoxic reaction on study also showed a dose-dependent reduction, with 46% experiencing a phototoxic reaction in the placebo group, as compared to only 19% in the 20 mg group and only 12% in the 60 mg group. We evaluated the patient-reported outcomes of global impression of change and global impression of severity. There was a dose-dependent improvement in the PGIC, reaching statistical significance in the 60 mg dose group. This improvement was on top of a notable improvement in the placebo group.
For the PGIS, there was improvement in bitopertin groups versus placebo, but this difference was not statistically significant. Regarding safety, there were no SAEs with bitopertin. Hemoglobin levels were stable, consistent with the BEACON data. There were 2 treatment-emergent adverse events leading to discontinuation, both in the 60 mg dose group, 1 due to dizziness and 1 due to a rash. Dizziness was more common in the 60 mg dose group. Most cases were mild, and the duration was short, with a median duration of 5 days. Now I'll hand it back to you, John.
Thank you, Will. So this phase II trial has given us a complex data set. We met our primary endpoint, demonstrating dose-dependent, statistically significant reductions in protoporphyrin IX compared to placebo in both the 20 mg and 60 mg dose groups. And therefore, in terms of mechanism, bitopertin is achieving the reduction of the disease-causative metabolite in these patients as expected. This is clearly a positive result. In terms of measures of light tolerance, we did see numerical increases in both dose groups relative to placebo. However, in all groups, including placebo, patients were spending quite a bit of time in light, and the strong performance of the placebo group rendered this endpoint not statistically significant, and frankly, a bit hard for us to interpret. There are pre-specified and clinically meaningful endpoints that performed well. We saw dose-dependent reductions in the rate of phototoxic reactions with pain.
This endpoint achieves statistical significance in the 60 mg dose group, with a reduction of 75% in the rate of pain attacks in that group relative to placebo. We also saw improvements in patients' quality of life. This was measured using the PGIC instrument, with over 85% of patients feeling much better in their disease status while on bitopertin. Also, safety was solid. Treatment was generally well-tolerated, with stable hemoglobin levels, and the safety data were generally consistent with what we saw before in the BEACON trial, as well as in the Roche safety database. So we have some endpoints where we are showing what we believe are clinically meaningful improvements for these patients, but we do have complexity that arises from the strong performance of the placebo group in our measures of light tolerance. This package of data is something we're going to have to sort through.
We plan to further evaluate the data internally, and we will be speaking to KOLs, patient advocacy groups, and regulators to map out a path forward. Now, I do want to spend a moment on the rest of our portfolio. We are excited about the growing data set in our hematology oncology programs, and we have a rich set of catalysts coming across the year. With respect to bitopertin, we do expect to be having regulatory interactions in the second half of the year as we unpack the data along the lines I discussed previously. Depending on regulatory feedback, we will plan development activities for 2025. We also have a study running in patients with Diamond-Blackfan anemia.
This is a distinct mechanism relying on reduction of heme rather than PP IX, and we anticipate some degree of phase II data initially reported in the second half of this year. Our second and third clinical programs are focused on iron metabolism. For DISC-0974, we expect to have updated phase Ib data from our myelofibrosis trial coming in the Q2 this year. And then the second half of the year, we expect to have data from both the myelofibrosis trial and the chronic kidney disease trial. And then we hope to be progressing into phase II on both indications. And finally, our third clinical program, DISC-3405, an iron restriction agent aiming first at polycythemia vera. And here we're in healthy volunteer studies.
We expect to be providing single ascending dose data in the first half of the year, followed by a complete phase I package by the end of the year. And of course, our entire portfolio is supported by a strong financial position with $360 million in cash reported at the end of 2023, and that funds all of these catalysts as well as our runway well into 2026. Finally, I want to thank everyone who participated in the AURORA study, with particular gratitude to the patients and families that participated here, as well as the investigators, the patient advocacy groups and the DISC team, all of whom did tremendous work to deliver what I believe is a very rigorous set of clinical results that will advance this field of drug development. And as I said, we look forward to further assessing these results and mapping out a path forward for the bitopertin program. So thank you all for your attention today, and I will turn it back over to our operator.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Thomas Smith with Leerink Partners. Your line is now open.
Hey, guys. Good morning. Thanks for taking the questions. Just a couple in terms of the patients that were enrolled here and a couple on the efficacy endpoints. Just in terms of the, the patients enrolled into AURORA, can you describe the baseline time to prodrome and cumulative light tolerance at baseline and describe how these patients compared to BEACON, as well as some of the other mid- and late-stage studies for Scenesse and dersimelagon? Just trying to get a sense of how these patients compared versus some of the other contemporary EPP studies.
Hey, Tom, this is John. Thanks for your question. I'll hand it over to Will Savage to answer that one.
So the baseline time to prodrome is similar in AURORA and BEACON and is consistent with the epidemiologic data as well as baseline characteristics in other EPP trials. In terms of daily light tolerance, you know, that's more difficult to assess in a short screening period. But it is, we have similar characteristics between BEACON and AURORA.
Understood. That's helpful. And then, I know it's early days with this data set, but, what do you believe could have driven the outsized placebo response in the light tolerance endpoints? Can you just talk about, I guess, any potential confounding factors or, you know, what, what do you think drove the, unexpected placebo response there?
Well, I think there was a lot of enthusiasm on the part of the patients who participated in the study. When you look at how quickly the, on our time to prodrome metric, how quickly sunlight tolerance increases, the first takeaway, I think, is that their patients are trying hard to improve their sunlight tolerance, and they're motivated to do so. We did do sensitivity analyses looking at baseline PPIX levels, baseline time to prodrome, seasonality of enrollment, and the geographic location of the site. None of those sensitivity analyses changed the association between active dose and placebo on our key secondary, which is not surprising because that's what randomized controlled trials do, is they eliminate confounding effects for baseline characteristics.
Got it. That's super helpful. And then just one last question, just on the path forward. How are you thinking about the timing for these additional analyses and for engaging with KOLs and regulators? And what are your current thoughts on what a potential next study might look like?
Yeah, thanks, Tom. Obviously, we're already working hard on those exact activities. Our guidance had been that we would have an end-of-phase two meeting in the second half of this year. That remains our objective. It may take a little longer, but on the granularity of a half a year, I think we'll still be on that track. And then that'll set up, obviously, trial activities next year. But the profile that we see here, you know, the issues in the key secondary endpoint notwithstanding, are that patients on drug have markedly reduced levels of the toxic metabolite. They're spending a lot of time in the sunlight. They're having very low, much decreased levels of phototoxic reactions, and almost everyone reporting feeling much better. So that's a profile we think we can explore and turn into a set of endpoints that we can, you know, develop reliably.
Got it. That makes a lot of sense. Thanks for taking the questions, guys. Appreciate it.
Thanks, Tom.
Thank you. Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open.
Hi, good morning. Thanks for taking my questions. The first is, can you just remind us—I, I think, you know, a lot of people say the regulatory precedent is in place in light of what we saw for Scenesse, but my understanding is at that time, that Clinuvel was the one that suggested that endpoint. And then, you know, maybe can you just speak to these endpoints in general and what you consistently hear is most clinically meaningful for patients? Thank you.
Yeah, thanks for the question, Kristen. That's a good one. It's an interesting field. As we look, you know, we look at it with a new eye in this data set. We've now concluded almost as much clinical work in this space as been done by other companies overall, and we're learning a lot. To the specific question about how this so-called key secondary and regulatory precedent was put together, I'll turn it over to you, Will.
Yeah. So looking at public records is discussion that Clinuvel had with FDA, where Clinuvel proposed this endpoint. It's. There was no workshop of KOLs and, you know, scientific endeavor that determined that the total time in light was the best endpoint to measure disease improvement. It's just the reason we put it as a key secondary is only because it was precedented, not necessarily because it's the best functioning endpoint. And the second question,
Yeah, it was just based on.
Take a guess in a little bit.
What is most clinically meaningful in your opinion?
Oh, yeah. Yeah.
Yeah.
Yeah. No, thank you. So, I think that pain is something that is meaningful to everybody. And clearly, when we're measuring these full phototoxic reactions, that is the most painful aspect of this disease, and that's what we're showing a dose-dependent reduction in and showing statistical significance on in the 60 mg dose group. Another way to tie that back actually to Tom's question is that everybody is spending more time in light on the study, but people in the placebo group seem to be doing it at a cost. So they spend more time in light, but there are more painful phototoxic reactions in that group than people on bitopertin. So, that data set seems to hang together in this initial look. We'll be looking further, but, you know, it seems that the most important painful aspect is improving on bitopertin.
Okay, thanks for that. I know you're still doing a lot of analysis, so I'm not sure if you can answer this question at this point, but, I mean, looking at some of the graphs here, it seems like more of the separation is taking place at a later time. So, you know, curious if you have any thoughts, if this was like a 6-month study, for example, over 4, if there would have been a little bit more of a separation on some of these endpoints. Thanks again.
Yeah, thanks for that question. No doubt, when you look at the data on its face, it does appear like you say, that, as you get to months 3 and 4, in particular, the 60 mg group is starting to separate more from the other treatment groups. So it does imply that a longer study would detect a larger difference between those groups. Although I say that, you know, that's just looking at the numbers. We can't obviously conclude that with any certainty based on these data, but it does suggest that a longer-term study would detect a larger difference.
Thank you.
Thank you. Our next question comes from the line of Malcolm Hoffman with BMO Capital Markets. Your line is now open.
Hi, guys, Malcolm Hoffman for Evan Seigerman. Thanks for taking our question. We wanted to ask for the ALT increases seen. It looks like the percentage of patients with increases were roughly similar across the placebo and treatment. We were curious to know if you had yet looked at average liver enzyme levels across treatment groups and whether you had seen any broad changes that may suggest any improvement from the decreased PPIX . Thanks.
Thanks for the question, Malcolm. Yeah, I'll hand it over to Will.
Yeah, so we don't have that data analyzed yet. I mean, you know, we were objective about what we reported in our AE table. It's just the number of AEs that are six or more across the study. And so we're not signaling anything about, you know, liver enzymes at this time. It's just we've chosen a numeric cutoff to include in the table.
Appreciate that. And then just a follow-up question, thinking about the historical placebo controls, obviously, that we had seen in the afamelanotide study. Is there any reason to think that the historical control may not be comparable relative to bitopertin? Just curious your thoughts there.
Yeah. So I think now as we look at this, you know, these results, try to kind of piece together what may have happened here, it's certainly in the realm of speculation. You know, it has been published for each of those agents that patients on those trials tended to be aware of the dose group that they're in, presumably on the basis of the tanning mechanisms for those agents. So patients can appreciate whether they are or not on active treatment. And that awareness may, you know, may influence the performance of the endpoint, whereas presumably in our study, there was more of a true blinding. There's no evident, I think, ability for patients to detect whether they're on or not on active therapy with bitopertin. So that is a difference that may explain some of the difference between the historical placebo performance and what we see in our trial here. That's just, you know, we're just kind of getting into this. Obviously, we'll be trying to figure that out in more detail.
Appreciate it. Thanks, guys.
Thank you. Our next question comes from the line of Rami Katkhouda with LifeSci Capital. Your line is now open.
Hey, guys. Thanks for taking my questions as well. Two quick ones for me. First, I guess, do you plan to advance the 20 mg dose into future studies? It seems like it had a better AE profile than the 60 mg dose, but didn't reach the 30% reduction from baseline in PPIX that has been associated with benefit in the past.
Hey, Rami. Yeah, thanks for the question. You know, I think looking at this data right now, if we just, you know, had to make a snap decision, the 60 mg dose is what we would progress with. I think the safety profile is great. There's no meaningful issues there. Across the two studies, BEACON and AURORA, there was one discontinuation in BEACON for headache at the 20 mg dose and one discontinuation in AURORA for dizziness at the 60 mg dose. That's just looking at the, you know, the two discontinuations that would seem to arise from the defined profile of the drug. So that's really not a meaningful level of discontinuation. Any of the safety issues around headaches and dizziness have, just as they were reported in the Roche safety databases, tended to be transient and low grade. So, you know, for all those reasons, 60 mgs looks great on the safety side and clearly is performing better on efficacy. So that would be the decision today, but this is something, you know, we do need to kind of build out our full approach here and the kind of endpoints we want to bring forward to the regulators, and that'll ultimately determine exactly which dose we bring forward.
Got it. And I guess I know it's early, but are there any measures you can implement in future studies to kind of mitigate the placebo rates, especially with regards to, cumulative time somewhat?
Yeah, well, again, we think that the endpoints that are performing well, that the number, the rate of phototoxic reactions, in particular, those are not showing a placebo issue. They're, they're showing kind of a robust drug effect. You know, interestingly, if you look back at the BEACON data, pooled on the pooled active arms relative to baseline, showed about a 90% reduction in phototoxic reactions. So we've seen that endpoint perform well and now, you know, show real distinction over the placebo group. So again, we're speaking on, you know, not complete analyses yet, but, but preliminarily, that endpoint certainly would appear to be both clinically meaningful and capable of distinguishing the drug effect over, placebo groups. So I think that's more the direction we're gonna go in.
I think coming back and trying to engineer the time and light endpoint to eliminate the placebo group, we may be able to do that. But I think, you know, we've already started coming up with ways you could administer that endpoint differently. But I'm not sure that's the preferred path to go down. I think, you know, the preferred path would be to kind of pick endpoints that have performed well and consistently over our two studies and engage with regulators to reach alignment that those are clinically meaningful endpoints. But again, this is kind of day one reaction.
Makes sense. Thank you.
Thank you. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open.
Hi, guys. Good morning. Thanks for the questions. I have two. So first, I just wanted to clarify. It sounds like you think, or you enroll the representative population, but you know, based on natural history data that we reviewed, it looks like maybe baseline sunlight tolerance was higher than would be expected. So is it possible that you didn't capture the right population here, or is it possible to design a study that enrolls a more severe patient population? And then I wondered if you could comment on the median total time and light without pain and how that compared to the mean data you presented. Thank you.
Hi, Danielle. Yeah, thanks for the questions. Will, why don't you take that?
Sure. So, second question first, regarding median data, it, we haven't presented that, that we will be presenting that data later. We're presenting what was programmed for our top-line analysis, the least squares means duration. But you know, when looked in number of ways, the relationship is similar. Regarding the representative nature of the population, you know, we picked baseline sunlight tolerance plus or minus 30 minutes, and it is true that there are more patients who have more than 30 minutes of sunlight tolerance as measured by baseline, but the median in the dataset is somewhere in the thirties. So if we picked, you know, post-hoc, a median of, like, somewhere 35 minutes, we would have above and below 35 minutes. It's not that the population is skewed towards milder, it's just the clustering of the population around 30 and coming down just a couple minutes short of the true median makes that difference apparent.
Understood. Thank you.
Thank you. Our next question comes from the line of Ben Burnett with Stifel. Your line is now open.
Hey, great. Thank you. It's my understanding that there's an open label, kind of a extension study beyond AURORA. Do you have a sense for kind of what the enrollment rate is into that extension study?
Hey, Ben. Thanks for the question. That's obviously we do have some sense for how that's going. You know, I think there's been very solid enrollment into that. And that's a data set we will be drawing from to enrich, again, the pool of data that's available for how this drug performs in these patients. But at this point, we haven't disclosed any specific numbers around that.
Okay, understood. And I guess also just wanna kind of dig into the sort of placebo effect that was seen in the cumulative time in sunlight. Like, did you have a sense of patients sort of pushed themselves early just 'cause they're, I don't know, maybe excited to be on a study? Or did the sunlight tolerance data sort of accumulate at a similar rate, sort of similar cadence as the drug arm?
Yeah. Will, you wanna take that?
Yeah. So, in broad strokes, they accumulate at similar rates, but this is a very first look, and there's a number of analyses that we need to do, to see where performance may differ between the groups. I mean, there is a consistent, numerically superior total time and light on both those groups versus placebo. So, there, we believe there's activity underneath that. It's just gonna take some time to parse that out.
Understood. Okay, and maybe just last question here. Could you remind us? So I think you showed us some interesting data on the incidence of phototoxic reactions, but how, how does that compare to afamelanotide?
Well, there's not really clear data from afamelanotide on the number of phototoxic reactions. So there's not, you know, an immediate comparison that we can make.
Okay. Okay, thanks so much.
Thanks.
Thank you. Our next question comes from the line of Jeffrey Hung with Morgan Stanley. Your line is now open.
Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions. Why do you think you saw a greater improvement on mean cumulative 4-month total time in light without pain at the 20 mg dose versus the 60 mg dose, especially considering the 60 mg arm yielded a greater PPIX reduction? Is there a potential that at the 60 mg dose, it was just more like a severe disease presentation or potentially the higher baseline PPIX levels? Any comments there? Thank you so much.
Yeah, thanks for the question. Will, you wanna handle that?
Sure. I mean, this is, of course, a question we're gonna be looking into. We don't have an answer today why that is, but there's a rich data set that will be coming forth that we will dig into.
Thank you.
Thank you. Our next question comes from the line of Douglas Tsao with H.C. Wainwright. Your line is now open.
Hi, good morning. Thanks for taking the questions. Just trying to understand a little bit around the time course and what you've seen. I'm just curious, in terms of the phototoxic reactions, have you been able to look at the data and see how those change over time relative to placebo?
Thanks for the question, Doug. Yeah, Will, go ahead.
Yeah, I mean, there is, that is, an analysis that we're gonna wanna do as well. We don't have that ready today, but that is an important question, the dynamics of phototoxic reactions and seeing that the timing of them makes sense and that, you know, whether there are other characteristics that can predict who's responding and how much.
Okay, great. And then just to.
So I was gonna add to that. If, you know, if you look at the slide that has that data on it, you know, you can see that at baseline, if anything, the treatment arms had a higher rate of phototoxic events during the baseline period. And then, of course, achieved a much, you know, dramatically lesser rate during the four months of treatment. And it's important, as you're looking at that table, to think about the baseline screening period as being quite a bit shorter than the four months of active treatment. So that's, you know, interesting and obviously encouraging, and we'll be looking into more detail, like Will said. Sorry, you were about to ask a second question.
No, no, no, John, and, and that's really helpful. And then, just also in terms of your sense now, when you look across this, the AURORA as well as the BEACON data, how quickly does the reduction in PPIX levels translate into improved sunlight tolerance to the best of your ability to sort of assess that? And I know there's gonna be some variability from patient to patient, but if you have a sense of, like, it seems that after X number of weeks, patients begin to be able to tolerate light better. Thank you.
Yeah. Will, you wanna go ahead?
Sure. So what's apparent when you look at our time to prodrome data is that there's that enthusiasm of the study participants we mentioned, becomes apparent within the first week of the study. I think there is also a, a treatment effect that also contributes to light tolerance, but using that light tolerance endpoint, it becomes difficult to parse out what is drug effect and what is patient enthusiasm. So it's something that's gonna require more analysis, and also, again, highlights that there are other endpoints that are needed to, you know, capture the full light tolerance experience.
Okay, great. Thank you so much.
Thanks, Doug.
Thank you. I'm showing no further questions at this time. I'd like to hand the call back over to John Quisel for closing remarks.
Great. Well, thank you everyone for your attention today. Obviously, what you've heard here is top-line data. We will be doing considerable analysis as well as consultations with experts, and patient groups to map out our path back to the regulators here. So thanks again for your time today. Goodbye.
This concludes today's conference call. Thank you for your participation. You may now disconnect.