Welcome everyone to the Ascelia Pharma conference call, where we will update you on the new agenda plan for SPARKLE conclusion. Earlier today we sent out a press release, and here on this call, we will go into more depth. With me today on this call, I have Julie Waras Brogren, Deputy CEO and Chief Commercial Officer, Andreas Norlin, Chief Scientific Officer, and Anton Hansson, Chief Financial Officer. Flip to slide number 2. During this presentation, we will be making a number of forward-looking statements, so please pay attention to the statement here. Now please move to slide number 3. Ascelia Pharma is dedicated to improve the life of people living with cancer by offering better treatment options, and particularly focused on rare cancer conditions.
Our business model is to identify, develop, and commercialize novel drugs that address unmet medical needs within the orphan oncology area. We have two drugs in clinical development. Orviglance, which we will be the sort of the center of attention today, is in an ongoing Phase III clinical study . It will be the only product in an addressable market of $500–600 million annually. Oncoral is ready to start phase 2 in the treatment of gastric cancer based on encouraging results in phase 1 and a high level of unmet medical need. We're based in Malmö, Sweden, and are listed on Nasdaq. We have a strong balance sheet and are funded into Q4 2023, including completion of the Orviglance phase 3 program. Please turn to page 4. As we have communicated earlier today, Orviglance has...
Previously, Orviglance has demonstrated strong data in the clinical phase I and II studies. We have completed a thorough analysis of Orviglance's data based in particular on the reread of Study 4 , while incorporating new internal and external data which has resulted in a very high effective level. The consequence of this is that we can start our study with substantially less patients than previously expected. These results on efficacy have been discussed with the FDA in the context of reducing the size of the SPARKLE study. Based on those discussions, we have decided to reduce the patient enrollment target of this from 200 to 80 patients. This means we expect SPARKLE patient enrollment by February or March 2023, and topline results in mid-2023 .
We also want to emphasize that this is not based on any data from the SPARKLE study itself, as we don't know the data yet . That is blinded. Now please turn to page number 5. The original SPARKLE design was based on the best information available at the time. This included Phase I and II studies, as well as data in literature. Although the data available at the time was, still is encouraging, it was based on conservative assumptions for the statistical test to create a comfortable margin to be likely to achieve a positive statistically significant result in this study. In particular, uncertainties related to dose level, as some of the earlier ones were done with different protocols, inclusion of primary liver cancer patients. Our earlier studies had metastasis patients. As well as changes in MRI instrumentation and imaging sequences, and inter-reader variability were factored into our assumptions.
The feasibility analysis we conducted in the pre-COVID setting with potential participating hospitals showed a total enrollment period of 9-12 months in a conservative estimate, and hence supporting making conservative assumptions in the absence of some evidence. Our new data is creating new evidence. It's partly based on the reread of the study at Karolinska using a similar three radiologist reading setup on all the available images from that study, and a similar scoring of the endpoints on the same scale as since point. That becomes a much more accurate predictor for overall efficacy in SPARKLE. Measured in SPARKLE context, the effect level in this study was 2-3 times the effect level that we had conservatively assumed in SPARKLE.
In fact, for the lesion visualization endpoint, which is the primary endpoint in SPARKLE, the p-value in this study with three readers was less than 0.009 in all 20 patients. This is typically regarded as a highly statistically significant result. It's a phase III endpoint in only 20 patients. This supports an encouraging efficacy profile of Orviglance. For the other important assumptions in the SPARKLE study design, other internal and external data which is available now to assess if we get a driven change in the statistical assumption, unexpected efficacy. In conclusion, the new data have been thoroughly analyzed, including with support from external and international experts, and still with conservative assumptions support a successful outcome of SPARKLE with substantially fewer patients than previously planned. This is presented to the FDA.
Based on the discussion and the feedback, we have decided to stop enrollment at 80 patients in SPARKLE, which is expected in February or March next year. Please turn to page 6. Although SPARKLE is not completed yet, I'd like to share the key challenges we faced during the SPARKLE trial and that we have updated you on, unfortunately with mixed news. When I speak to colleagues in drug development, many share similar stories in development. It has been significantly more difficult to enroll into SPARKLE than initially planned. We knew it was an orphan condition, and SPARKLE is a very large orphan drug study. It's also complicated to recruit only a small subset of patients who undergo a procedure, so we're looking only for the patients with severe renal impairment undergoing a liver MRI. It's not easy for investigators to be...
Right, to meet the patient at a time in the patient diagnosis treatment, so that they are available to join SPARKLE. This is all a major difference compared to routine clinical practice, where the enrollment criteria or usage of the drugs is very different. SPARKLE was started immediately before the COVID pandemic hit Europe and U.S. in 2020. The study never really got going where all the participating sites began attending to an overload of COVID patients and were unable to recruit patients in SPARKLE and other clinical studies . To complicate matters further, our CRO experienced liquidity issues as we announced back then. During the worst, we initiated a process to select a new CRO, which was up and running back towards the end of 2020, just in time the next COVID lockdown in the winter of 2021.
COVID has continued to play a significant role in SPARKLE and many other studies. This day is less direct in terms of overload of patients in hospital, one of the key consequences have been that many hospital backlogs , including SPARKLE sites, means that they're unable to be enrolling patients. One of our immediate factors was to open more sites in Russia as hospitals weren't overwhelmed with COVID patients. During 2021, we added a large number of hospitals, at the end of March 2022, we suspended all 13 Russian sites due to invasion of Ukraine. As you all know, this has been an unprecedented and challenging period. We look forward to completing the SPARKLE enrollment very soon. Please turn to page number 7.
Close to completing the SPARKLE enrollment. We're seeing an uptick in the trend, as well as having sites that have been unable to enroll but are now finding patients. Technically, we have 48 active sites. Only 23 of them have enrolled so far. Some of the sites have been recently opened. Some have been active for a period of time. Excuse me. As of the end of last week, we have 58 patients completed. The pool of patients identified and whom they shortly joined SPARKLE is significantly larger than we've seen previously. One of our patient recruitment initiatives is to work with the patient organization for potentially eligible patients with glioma through social media. Last week, the first patient for this initiative was consented, although not enrolled. Not part of the 58.
We hope for more soon. We've been frequently asked about the status on the enrollment, and our policy has been to announce the last patients. We understand this has been tiring on investors' patience, and we've decided to change this policy for the remainder to announce the number of patients after the last Friday of each month, so you can follow the progress on a regular basis. Now please turn to slide number 8. Today, we've completed 8 studies with Orviglance. SPARKLE will be number 9. The results have been showing consistent, strong safety and profile. The Phase II data and trials analyzed individually, as well as in a study which showed 33% increase in lesions detected and highly significant results on lesion visualization.
In the Orviglance study comparing Orviglance to liver-specific Avastin maintenance, and we just scored very high when evaluating Orviglance, both in MRI , but also liver-specific contrast agents . As you may recall, these patients had normal scans at extremely low risk for opportunistic systemic hypoxia. Recently, we completed the food effect studies which showed that patients had a good liver enhancement, both when fasting before Orviglance administration and also when having a light meal prior to Orviglance administration. This will hopefully make it even more attractive for patients in clinical practice. We have also completed a study in patients with various degrees of liver disease, demonstrating that Orviglance was enhanced in liver MRI in all categories of liver impairment. Importantly, the study showed that even in patients with severe liver impairment, there's practically no excretion of the kidney.
Everything goes to the liver and the bile, which further support that Orviglance is a product with a target population. Please turn to page 9. I'd also like to update you on a couple of other aspects of Orviglance. As is customary in many trial Data Safety Monitoring Board, which reviews the safety profile of the drug when a certain number of patients have been enrolled to look for unexpected side effects. In SPARKLE, this review was that 30 patients had been enrolled. The conclusion was that the trial could proceed, no serious adverse events, and the most frequently noted side effect was nausea, which was 5 patients out of the 30. This profile is consistent with earlier studies. Biologically, children are not small adults, therefore a special program is needed to obtain approval in children.
For the FDA, it is waived due to the Orphan Drug Designation, and it's not targeting a pediatric disease. For Europe, we have agreed with the EMA to conduct a clinical study in the adult indication. The manufacturing is highly important for both the regulatory process and the commercialization. We're manufacturing and have decided to support the getting to the end. Our activities in manufacturing support the timeline for regulatory activities. Please turn to page number 10. I would like to end with our two key milestones ahead. We expect the patient enrollment to be in February or March next year. This will allow us to generate topline results around mid-2023, when all the data have been evaluated and probably you would say quality statistical analysis completed.
We're highly encouraged by the strong efficacy seen in the new statistical analysis of the existing data. Our confidence in a successful study is strong, and we highly value the constructive dialogue with the FDA. The insight and senior team members work very hard to complete SPARKLE, despite the substantial structural sector challenge during the COVID pandemic, and we are
Thank you. If you wish to ask a question, please press 01 on your telephone keypad. If you wish to withdraw your question, you may do so by pressing 02 to cancel. There'll be a brief pause while questions are being uncertain. Our first question comes from Thomas Bowers from Danske Bank. Please go ahead. Your line is now open.
Yes, thank you. It was a poor line, did I hear correctly that the reason for the cut in the target from 200 to 80 patients, is that the data from any particular trial, or what's the reason, basically?
Yeah. Thank you for the question. I hope you hear better now. The reason was that when we did the reread with the same readers as we did the study, the efficacy data was very strong. That we have obviously been testing very, very strong with all our capacity internally and externally to make sure that that was a credible result. We don't wanna change or reduce the size of the study, as it's fully warranted. We don't wanna compromise, you would say, likelihood of success.
That is, I would say, a key data point for reducing the size of data that has become available year and a half, both internal and external data that helps us reduce some of the uncertainties that was involved in the initial sizing of the SPARKLE trial.
So the statistical hypothesis for the primary thick example, that's the same?
Yeah.
Okay. What makes you confident, in terms of the conclusion of the trial with this new enrollment target?
What we're seeing, as mentioned, is that we see taking the trend, we see more sites actually being and recruiting. There's also, you know, there's always a, let's say, a pool of patients that are hopefully about to end the study. That pool of patients is larger than significantly larger than we've seen before. We have, you know, good dialogue with more and more investigators and also, you know, it's complicated for radiologists in a routine clinical practice and even in a academic center to conduct, be responsible for doing a clinical trial in radiology. That's one of the things we've learned because they're usually having patients coming in, doing a scan and then out, not seeing them again.
Here, this requires them to have a dialogue with the patient, consent the patient, and inform them about the trial. When we do the trial, they need to do a lot more, you would say, blood sampling and other tests and assessments, which is just, you know, very different burden on. Once a site has recruited the first patient, they've learned how to do this. That is very important, as we've seen in terms of getting more patients into the trial. The first patient has been a big hurdle for many of the sites. That makes us confident that we can bring the patient population or the enrollment to 80 patients in February, March next year.
Okay. Thank you.
Your line is. Thank you. The next question comes from Sten Westerberg from. Please go ahead. Line is now open.
Thank you. Good morning. You're referring to a new statistical analysis on data on the imaging, image reading methodology that you're making use of. Is this published data?
Yeah. Josh, you wanna answer?
Yeah.
This is Andreas Norlin, Chief Scientific Officer. The data is partially published. We have presented it at the RSNA in May in 2021. Not all of the data was presented there. We have done additional analysis after that. As Magnus mentioned before, we have done this very thoroughly because we really wanted to be sure that this is something that we can be confident in. The short answer is partially published.
The data you're referring to, is this data on Orviglance or some other contrast agent?
It's Orviglance.
Okay. Second question. Since you had quite a few recruiting centers for more than 1 year and so far achieved assignment of 58 patients, the question arises, to what extent the recruitment pace is a sign of the scarcity of these patients with kidney disease and liver damages?
Julie, do you want to?
Yes.
talk about that?
Thank you for this question. Overall, our confident commercial potential is unchanged, and a lot of the dialogue with these investigators helps us in our pre-launch activities. The thing is that research and trial recruitment is quite different from clinical practice. Actually, there's some data showing that, for example, only 1 out of 20 eligible patients are actually recruited into a relevant clinical study. We know that they are population, and they have multiple complications, so they are at the bigger hospitals, which is a good thing for us commercially. The big hospitals typically are quite focused on the clinical practice in the community rather than more research-based activities. Overall, this doesn't change our confidence in the commercial potential of Orviglance.
Okay. Will the finish of the SPARKLE study in any way accelerate your cash burn during the start of next year?
No. I mean, we still maintain the guidance that we have funding until Q4 next year.
Mm-hmm. Okay. Final question. Sorry if I have a lot of questions, but, final question, is there any other changes? I mean, you're maintaining the statistical power now at 80 patients, but are there any other changes to the protocol of the SPARKLE study?
No. There's nothing.
Okay. Okay, thank you. That concludes my questions.
Yeah, that's great. Thank you for the questions, Sten.
Thank you. A reminder, if you wish to ask a question, please press zero one on your telephone keypad. The next question comes from Fredrik Thor from Redeye. Please go ahead. Your line is now open.
Thank you for taking my questions. Mainly, clarification. We should understand the reason for this change as the foundation is the data from an earlier study, and you used the methodology, the review, which is aligned to the SPARKLE pivotal study. The main change is that you use the same approach to review this existing data.
Yeah. That's absolutely correct, Johan. It's the same reading, the same annotation, because it's we've not used that specific three-reader setup, which is also more expensive, we've not used that in the earlier studies. Now we have that for one of the studies and that demonstrates a very strong efficacy.
The reference to the efficacy, of course, it's natural then to compare with the phase II results and this finding based on 20 patients suggests that, well, you're in a position to go beyond that.
Yeah. You could say, if we've had this data from the very beginning, there would have been no doubt that this is how we would have designed SPARKLE from the beginning. That's how we've been sampled. Wish we had had that data from the beginning, but we didn't. Now we have it, we've had the dialogue with the FDA after-.
Yeah.
let's say, cross-checking and challenging the data, very intensely internally before having that FDA dialogue. Based on that dialogue, we decided to stop enrollment at 80, which we think is, will give us a very good opportunity to have a positive outcome of the study.
Excellent. That brings us to the next question then, because it was fairly recently, you still aimed at up to 200 by end of 2022, even if that was, of course, challenging. This review process time with the FDA, presumably that's been taking quite a long time.
Yeah. You're right, Johan. As you know, first of all, we spend a lot of time and both internally and externally to make sure the data was rock solid when, you know, the high level of efficacy. Then having the with the FDA, as you are well aware, is not just sending an email across. It's requesting a meeting, and there are certain schedules and notice periods for that, and putting in a full significant briefing package with a lot of documents, then having the meeting. Then once the meeting has been held, we need to wait for the final minutes because those are the ones that sort of determine what was agreed.
That we got very recently, and then we've been able to make the decision to start the study at 80 patients.
I mean, statistical significance and the power, it, I mean, is based on the efficacy and also the number. Should we understand this as being a sort of similar significance as is based on 200, but now with the, what looks like a stronger efficacy, so you don't require as many patients?
Yeah. Yes. I think, again, the simple and straight answer is yes. We basically don't think that we are changing the likelihood of showing a significance. Because the data appears to be stronger than we initially assumed.
The next point of patient update will come just before NF2 then?
Yeah.
Excellent. Thank you. Look forward-
Yeah. Just to explain. We were getting updates from the CRO who's having the data. Once we have the information from the CRO, and that is quality checked, then we will send it out in the first place. Everyone can sort of follow the enrollment progress.
Very good. Okay. Thank you very much.
Yeah. Thank you.
That's all from me.
Thank you. The next question comes from Sten Westerberg from Analysguiden. Please go ahead. Your line is now open.
Yeah, if I may follow up the question and what you're referring to as a two to three times more efficient level for Orviglance in previous studies. Sounds like a pretty dramatic improvement just by re-reading historical data. Perhaps if you could dig somewhat more into the reason for why you suddenly see a two to three times more efficient readout from the substance?
Yes, good question. The 2,000-3,000 times higher effect that we have seen with this re-read refers to what we assume when we mentioned or made the calculation of the sample size for the SPARKLE study. One of the big uncertainties that went into the calculation, the original calculations, were that we didn't know anything about inter-reader variability. That's the reason why you need to have three readers when you do the kind of readout study like SPARKLE. It's according to FDA guidelines. That was one of the factors that we used.
Even though the data we had at the time was very encouraging and it showed significant effects, it was the prudent time just to make sure that we could deliver on the study. With this new information we have from the re-read, we have information about differences readers and what that might mean. With that, we are more confident to conclude that we can assume a higher effect than what we did originally. It's important to emphasize that we still have some margin. We have also included quite conservative assumptions about the effect of those differences, the effect of primary liver tumors than before.
Okay. It's a pretty bad line. Did you mention inter-reader variability?
Exactly. So we have. The way you do this is you have three radiologists that independently of each other make an assessment of the images from the patients and compare pre and post-contrast image quality and the. And there is a scoring system to do that. And there, of course, there may be differences between radiologists in how they score lesions. And that's the kind of uncertainty that we didn't have any information about from the beginning. But now we have that, and that is what we have implemented. And despite that, we believe that we have a more that the efficacy is higher than earlier anticipated.
Okay. Just to understand this again, you're expecting less inter-reader variability from these three radiologists in the SPARKLE study, and that is the main reason why you dare to take one...
We understand the variability much better. In the original assumption, we were very conservative because we did not know how much the variability would be. Now we have a much better information on that and can take that into account. There are still variabilities, there are still differences between readers, and that is as expected. That is not the only reason. We also have other information that I also mentioned, by Magnus, new information, both internal and external, about, the other assumptions that are done into this updated estimate.
Okay. Thank you so much.
Thank you.
Thank you. There are no more questions from the telephone conference. I'll hand over the word back to you, Magnus.
Yeah. Thank you everyone for listening in to our update. Thank you for all the questions. We apologize for the bad line. Hopefully, you've been able to hear most of it anyway. Thank you, and have a good day.