Yes. Thank you, operator, and welcome everyone to the webcast to report Ascelia Pharma's Q4 Report in 2021. I'm Magnus Corfitzen, CEO of Ascelia Pharma. With me today, I have Kristian Borbos, our Chief Financial Officer, Julie Waras Brogren, our Chief Commercial Officer, and Andreas Norlin, VP of R&D. Our regular followers will notice that Andreas has joined instead of our Chief Medical Officer, Carl Bjartmar on this call. This is a temporary support we have here as Carl is traveling and right now meeting with an investigator in the SPARKLE study. We're really happy to have Andreas joining us today. Now please turn to page 2. We'll be making certain forward-looking statements on this call, so please pay close attention to this before moving to slide three.
Ascelia Pharma is dedicated to improve the life of people living with cancer by offering better treatment options. In particular, we focus on rare cancer conditions. Our business model is to identify, develop, and commercialize novel drugs that address unmet medical needs within orphan oncology. We have two drugs in clinical development. Orviglance, formerly known as Mangoral, is in an ongoing phase III clinical study. It will be the only product targeting an addressable market of $500 million-$600 million annually. Oncoral is starting the phase II clinical study in the treatment of gastric cancer based on encouraging results in phase I. We're based in Malmö, Sweden, and are listed on Nasdaq Stockholm. We have a strong balance sheet and are funded into 2023, including completion of the phase III program for Orviglance. Now please turn to page four.
Ascelia Pharma is in its transformative phase as we're moving from late-stage development into commercial stage. Next year, we will start to generate revenue from our commercial operations in the US when Orviglance has been launched. As part of our strategy, we expect to have expanded our portfolio by acquiring or in-licensing an additional drug that fit our orphan oncology strategy and where we can make significant benefit for the patients. In 2025, we expect to have established Orviglance as the market leader in this market, Oncoral in phase III development, and having one or two more clinical-stage assets in the pipeline through acquisitions or in-licensing. This is an exciting time for Ascelia Pharma, and we see tremendous value creation potential as we progress. Please move to page five. In Q4 last year, we continued to make progress.
In October, we announced the last patient last visit in the food effect study, and hence the clinical part of the study was completed. In December, Dr. Kohkan Shamsi presented data at RSNA, the world's largest radiology conference taking place in Chicago, that compared Orviglance with a liver-specific gadolinium contrast agent. Also in December last year, the FDA approved the IND application for Oncoral and the phase II clinical study. I'll go into these new drugs in the next few slides, so please turn to slide number six. Orviglance is orally administered, that is, it's mixed with water and drunk by the patient. Up until now, the patients have been fasting before getting Orviglance, which is the usual approach for such a product.
The food effect study investigates what happens to the uptake and the absorption of Orviglance, including the safety if the patient has had something to eat before taking Orviglance. In this study, we tested in two arms, one with a full breakfast as defined by the FDA guidelines, and one with sort of a light breakfast or a so-called snack. The preliminary data that we have released indicate Orviglance was well-tolerated, and we expect to be able to announce the final results this quarter. The data from this study will be part of the NDA submission for approval and will also make it more convenient for the patient in case fasting is not a requirement, but we do not know this, whether this is the case yet.
This type of study is required for all the administered drugs to understand if there is interaction with food on the safety and efficacy. We're looking very much forward to completing the data analysis and share the results. Now please move to page number seven. At RSNA in December 2021, Dr. Kohkan Shamsi presented more data on Orviglance. We have previously announced top-line data from this study, and at this presentation, more details were shared. The imaging was done years back at a clinical study at Karolinska Hospital in Stockholm in patients with normal kidney function. This allowed us to make a head-to-head comparison with the liver-specific gadolinium agent MultiHance.
As you all know, due to the safety profile of gadolinium and the black box warning on all gadolinium products, such a study is not feasible in the target population for Orviglance because of risk of nephrogenic systemic fibrosis. The results that we share here include that, you can say, what is shown on these slides. All the images were evaluated by three independent radiologists based on a prospective protocol similar to the SPARKLE. The results were three out of three readers detected more lesions with Orviglance than with MultiHance. Three out of three readers saw smaller lesions with Orviglance. Two out of three readers reported higher lesion border delineation with Orviglance, and two out of three readers reported higher lesion contrast to Orviglance. The study was only in 20 patients and hence not powered to show statistical significance.
However, we think it clearly supports an attractive profile for Orviglance and will strengthen the data package towards radiologists, regulators, and payers. Now please move to page eight. In December, we also announced the FDA approval of our IND filing for Oncoral.
This is very positive as this is the first time the FDA have reviewed Oncoral documentation and also the phase II study design. The initial dose escalation phase of the study will be conducted at hospitals in Europe, and hence we also need regulatory approval in these individual countries where the hospitals are located. Once the dose has been established, U.S. hospitals will also be involved in recruitment of patients. We expect the first patients first visits to be in Q2 or Q3 this year. Now please move to page number nine. Now we go into more depth on our pipeline, and I'd like to hand over the work to our VP of R&D, Andreas Norlin.
Yes. Thank you, Magnus. Yeah, we're on slide 10. Orviglance is a novel oral contrast agent for liver MRI, which addresses a very specific unmet medical need. The contrast agents available today are all based on gadolinium, a heavy metal, and gadolinium should not be given to patients with poor kidney function since it is excreted through the kidneys and slow elimination can cause serious side effects. In the future, this unmet need can be met by Orviglance. This specific target population is approximately 4% of all patients requiring a liver MRI, which corresponds to an addressable market of $500 million-$600 million annually in the major markets. The right side of the slide shows how Orviglance works in a patient with colorectal cancer.
The left picture shows an unenhanced MRI scan without the contrast agent, which is a standard procedure today for our target population. The right scan shows the same patient after administration of Orviglance. The liver has taken up Orviglance and appears bright. There is one dark area highlighted here that is only visible after Orviglance enhancement. This is a metastasis which would not have been detected without the contrast agent. This illustrates the importance of the contrast agent. In this case, since detected and localized, the metastasis may be removed which significantly improve prognosis for the patient. We have made good progress. A thorough phase I and phase II program has been completed with strong data providing clinical proof of concept, and we are currently in phase III.
We should also mention that the development is validated and aided by an orphan drug designation by the FDA. The next slide, please. Slide 11. As mentioned, there is a strong clinical proof of concept through six individual phase I and II studies with very consistent results. These data were confirmed by an independent re-analysis by a blinded reader, which showed highly significant effects on endpoints that are also used in the ongoing phase III study. The primary phase III endpoint is lesion visualization based on the co-primary parameters lesion delineation and lesion contrast compared to background. As seen on the slide, both these were highly significant in the phase II program. It was also noted that 33% more metastases were detected with Orviglance compared to unenhanced MRI.
The existing data also contains a direct comparison to a gadolinium-based liver contrast agent, which demonstrated similar effects on lesion visualizations, as we just heard. These results were, as mentioned earlier, presented at RSNA in December last year. Next slide, please. Slide 12. Our ongoing registration study, SPARKLE, investigates the efficacy and safety of Orviglance in the target population with focal liver lesions and poor kidney function. The study, which is a global study with 200 patients, currently have more than four sites open in U.S., Europe, and Latin America. Since there is no available contrast agent for patients with impaired renal function, the comparator will be unenhanced MRI, which is currently the standard procedure in these patients. This study design has been agreed with FDA and EMA.
The strategy is to repeat and confirm the phase II results using the same endpoints, lesion border delineation and conspicuity. It should also be mentioned that the follow-up for each patient is very short compared to most clinical studies, and this simplifies the operational procedure, and we will also have final data relatively sooner than in a typical phase III study. Next slide, please.
Thank you, Andreas. We are now on slide 13. The addressable market for Orviglance is estimated to represent $500 million-$600 million annually in our key markets, the U.S., Europe, and Japan. This potential is based on the volume of procedures for patients with cancer in the liver and poor kidney function falling under the black box warning by the regulatory authorities. We have real-world data supporting our volume estimates for patients and the number of procedures per patient. We have researched price points and the evidence required by payers to support a strong value proposition. Building our own commercial team in the U.S. allows us to create an attractive top line and retain profit and value in the company. For other markets, starting with Europe and Japan, our strategy is to maximize the value of Orviglance by working with partners. Please move on to slide 14.
For the U.S., the attractiveness and clear path to market is a really strong case for us to commercialize Orviglance on our own. We are preparing to grow and build a U.S. commercial affiliate. The target patient population for Orviglance has multiple health complications. They have suspected cancer in the liver, and they have poor kidney function. This means that the main decision-makers for using Orviglance are centered around 400 hospitals and sites in the U.S. Therefore, a focus team in an affiliate of around 40 FTE can reach priority decision-makers at launch. We now have our U.S. office established, which represents an important step to engage more closely with key stakeholders and with the clinical community on the journey to make Orviglance available to patients and physicians in the U.S. Our global manufacturing partner, Cambrex, is also in New Jersey.
We have gradually built our footprint and relationship with key stakeholders as part of our preparations for launch. This includes a number of leading radiologists that are part of our phase III study investigators. Please move to slide 15.
Yes, thank you, Julie. I will continue again and tell a little bit more about Oncoral. Please move to slide 16. The active substance of Oncoral is irinotecan, an established chemotherapy with well-documented anticancer effects. It is currently used in several solid cancer indications and is approved for colorectal cancer and pancreatic cancer. In Japan, it is also approved for gastric cancer. Today, the administration is intravenous bolus infusion, typically every third week and typically high dose. Oncoral is a novel oral formulation of irinotecan. The tablet formulation enables more frequent daily dosing that could offer several potential advantages, most important, efficacy. It is well known that many cancer types have suboptimal treatment outcomes today.
An oral daily dosing may improve efficacy through a favorable pharmacokinetic and pharmacodynamic profile based on more constant therapeutic plasma levels of the active substance, and there are both non-clinical and clinical data supporting this concept. There is tolerability or safety. Intravenous dosing of chemotherapy is frequently associated with severe side effects, typically gastrointestinal and hematological. An oral daily dosing has the potential for improved tolerability by avoiding high plasma levels and by offering dosing flexibility. In addition, there is potential convenience and cost benefits. It is more convenient and cost-effective to take a tablet at home than going into the hospital and prepare for an intravenous administration. Slide 17, please. The concept of frequent low-dose administration is called metronomic dosing.
The figure to the left illustrates a simulation model comparing levels of the active metabolite SN-38 after irinotecan IV dosing every third week, the gray line, and oral Oncoral dose daily, the orange line. Over a three-week cycle, the exposure or AUC is comparable, although the plasma peaks associated with toxicity are avoided by daily dosing. Approximately 1/3 of the side effects observed after intravenous dosing are recorded as severe or even life-threatening, grade three or four. Metronomic dosing may not only reduce the peak-related toxicity but also brings the possibility to adjust dosing quickly if adverse events should occur. Our own Oncoral phase I results show that Oncoral was well-tolerated overall, and importantly, the hematological toxicities were mild to moderate, grade one or two. In addition, our phase I data with Oncoral indicated activity or stable disease even in patients that previously progressed on irinotecan given intravenously.
Slide 18, please. As an example of the potential efficacy benefits of lower, more frequent dosing of irinotecan, here you can see the results from a study in metastatic refractory breast cancer. Even a relatively modest change in dosing frequency, once weekly versus every third week, could improve the overall survival from 20%-32% in this study. Slide 19. We are preparing phase II. The objective of the phase II study is to generate a clinical proof of efficacy in metastatic gastric cancer, and the strategic reasons to choose gastric cancer are several. First, the clinical guidelines and clinical data support efficacy of irinotecan in gastric cancer. Secondly, gastric cancer is a severe cancer form with a high unmet need and a potential for orphan drug designation. Subsequently, there is potential for label expansion into other solid tumors in tumor indications.
Finally, as shown in the figure, there is data from gastric cancer animal models supporting a synergistic or additive effect of irinotecan if combined with LONSURF. LONSURF is another oral chemotherapy which was approved for metastatic gastric cancer in 2019. This all-oral combination could potentially provide a more potent treatment alternative for these patients. Next slide, please. Slide 20. This study is a randomized controlled multicenter multinational study comparing Oncoral on top of LONSURF with LONSURF alone. Primary endpoint is typical for phase II studies in oncology progression-free survival, and then a battery of secondary endpoints, response rates, PK, safety, and overall survival are included. The study will include approximately 100 patients, and we anticipate the study to start this year, continuing into 2024.
As have been announced before, we have entered into a clinical collaboration agreement with Taiho Oncology regarding supply of LONSURF to the study. Next slide, please.
Thank you. On slide 21. Gastric cancer is today a $3 billion market. Every year, more than 1 million people are diagnosed with gastric cancer. In the U.S. and Europe, gastric cancer is an orphan disease with more than 100,000 patients diagnosed every year. Many are diagnosed quite late, and around 60,000 of these receive drug treatment and progress to advanced stage. Gastric cancer is more common in Asian markets, where more than 500,000 people are diagnosed every year. Please move to slide 21. 22. Thank you. Why will we start in gastric cancer where there is a high unmet need and an opportunity for an open indication? We see opportunities for expanding development into other indications where a daily dose in tablet formulations can demonstrate an attractive efficacy and safety profile.
Irinotecan as an IV formulation is already approved in colorectal and pancreatic cancer. In addition, irinotecan is clinically demonstrated and recognized in the NCCN cancer care guidelines for many cancer types. We are assessing these opportunities as our phase II study progresses and as part of our ongoing strategic plans for our growth. Please move to slide 23.
Okay. Thank you, Julie. Please turn to page 24. The key message on the financials is that the liquid position continues to be strong and we have around SEK 262 million in the bank, which will take us into 2023. The cash position will primarily be used for ongoing phase III study as well as commercial preparations and, of course, also the upcoming Oncoral clinical study. Please turn to page 25. Here we see the development in earnings. Again, the key takeaway for the core as well as for the full year 2021 compared to previous year and those periods is the same as we discussed on earlier calls.
We see an increased loss year-over-year, which is as expected and reflects the increased R&D activity related to the Orviglance phase III study as well as commercial preparation, and again, also the phase II preparations for Oncoral. With that, I'll leave the word over to Magnus.
Yeah. Thank you, Kristian. I'd like to end this quarterly update with our focus on our two milestones. The clinical development of Orviglance is our key priority. We all know that there is a COVID impact. We've previously announced that, but we continue to work with the investigators and deal with the unusual circumstances to make this study a success. We're adapting as we progress to ensure patients, medical staff, employees and everybody else is safe, and we can complete the study in good shape. We expect to complete the enrollment in the first half of this year. We continue our preparations for Orviglance's commercialization and have many activities ongoing to enable us to detail and implement the value-maximizing strategy.
For the Oncoral phase II clinical study, we expect to be able to recruit the first patient for first visit in Q2 or Q3 this year. This was our final slide, and we'd be happy to take any questions.
Thank you. If you do wish to ask a question, please press zero one on your telephone keypad now. Our first question comes from the line of Ludwig Andersson from Erik Penser Bank. Please go ahead.
Yeah. Thank you. That's the only thing for the presentation. For my first one, you recently changed some of the inclusion criteria in the phase III study with Mangoral. Could you elaborate a bit on this and how it might affect both the patient recruitment but also a future label of the drug?
Thank you, Ludwig. Yes, you're absolutely correct. We recently implemented changes in the protocol to include hemodialysis patients. Patients on dialysis go to a dialysis center two-three times a week to clean the blood. Patients on dialysis have very poor kidney function. It's still within the target population that we had originally. Typically you don't include hemodialysis patients because it's more difficult to measure blood levels and so forth because they get this cleaning of the blood in a different way than the normal patient. It's an important part of the target population. It's also, from a patient recruitment strategy, you would say, easier to localize these patients because they, by definition, go to a dialysis center.
The density of potential SPARKLE patients and patients in the target population for Orviglance, they have a high density there. That's the reason why we have included that in the study. We think that's gonna, you could say, continue positive impact upon on patient recruitment in the SPARKLE study. We also included Child-Pugh B. Child-Pugh criteria relates to hepatic function, liver function. We have, from the beginning, had Child-Pugh A, so mild liver impairment. Now we also included moderate. We have the hepatic impairment study ongoing, and hopefully, we can complete that study in the not too distant future, that is investigating mild, moderate, and severe hepatic impairment.
Finally, we have made some changes to the follow-up schedule on the safety follow-up. As you may recall in the study on the day they are dosed and scanned, they spend a long time in the hospital, and there will be follow-up safety visits in the following days. We have added more flexibility on those safety follow-up visits. That is also very much in, say, related to COVID because patients are in general hesitant to go to the hospital in COVID times. I think that's also gonna be important for some patients.
Great. Thank you, Magnus. That's helpful. For my next question, I was wondering about the Oncoral study, the phase II study. As I understand, you have received an approval to initiate this, but you guide for a timeline where you will dose the first patient Q2, Q3 this year. Why is it that you're taking this long before you can dose the first patient?
Yeah. No, that's a very relevant question. We have the IND approval from December. In the initial phase of the study, we will do dose escalation. We have not in clinical studies any data that show how Oncoral and long-term dosing interacts. It's typically to have sort of a dose escalation phase where we start with the dosing, and then we escalate up and see how high we can go. Those sites that will do this are based in Europe, and we need to have you could say, national approval in those countries where those hospitals are before we can start dosing.
That is kind of a sequential process because we have had, I would say, a good deal of interaction with the FDA in terms of the IND process that has been valuable. We wanted to complete that and get that firmed up with the FDA before submitting to the national authorities in Europe. It is a sequential process. Probably takes some time. The single trial applications to those countries have been submitted in Europe, and there's a review process taking up to three months. Hopefully, that will be in good shape here, and then we can initiate the sites and get patients dosed.
All right. Perfect. I understand. That was everything for me. Thank you very much.
Yeah. Thank you, Ludwig.
The next question comes from the line of Johan Unnérus from Redeye. Please go ahead.
Thank you for taking our questions. First, a follow-up. Could you clarify if this change in protocol also could have an impact on the future label?
Yeah, no, it will be included in the previous label. What we are doing is, you would say, for instance, if we take the hemodialysis patients, then essentially what we're doing is we had a cap on how many hemodialysis patients we could have in the study. That cap, you would say, is eliminated. Now it's any patient with a GFR below 30, regardless of dialysis status. Per se, it would not be significantly impacting the label as such. On the Child-Pugh A, that would potentially, you would say, expand the label. It's something that you could say would be data-driven.
We're also doing the hepatic impairment study, and that data would also go into the label. Maybe there might be, you know, small changes depending on whether they are in the SPARKLE study or not.
Interesting. Presumably now in the sort of final part of recruitment, the patients that are being added is a high proportions coming from these, relating to these changes.
Yeah, that's what we hope. I mean, we're working with the sites all over and helping them on the recruitment barriers. I mean, this is many different countries, many different healthcare systems. Some sites have seen these as you could say significant barriers to patient recruitment. In others, less so. That is what we have essentially been doing all throughout the study, identifying, getting the feedback from the sites, understanding the dynamics and the patient flow, and then as much as we can adjust in a good way so we don't compromise, you could say the quality of the study and hopefully the outcome of the study. It's more the sort of helping making it easier for investigators to recruit patients.
This is a reflection of that. We have made a number of changes to the protocol, but we thought these were, you could say more significant. That's why we included it in this call report.
Very good. For each patient once recruited, the results will come within weeks. Then if we assume that the ambition will be fulfilled and if it's fully recruited, say in June, just as an illustration, when can we expect the formal results?
Yeah. Well, we are not guided on you know how long will it go from last patient last visit until we can announce the top-line results. You're absolutely right that the images are read at the hospital and evaluated there. What we have as the primary endpoint is that we take all the images into one database, and then we have three trained radiologists who will evaluate all the scans. This is kind of the gold standard evaluation by the FDA to minimize bias. We don't have a big variability whether the patient was recruited on an Italian site or a U.S. site, or you could say there's no site variability in the evaluation, which is important.
It's this centralized reading by the three independent radiologists that will be used for the primary endpoint. We need to wait for that centralized reading. You could say the process is such that we are doing those reads in batches. We're doing that in parallel with the study. We're not waiting to complete the full study before initiating the evaluation. We are doing that in parallel. When the last, you could say, batch of patients have been recruited in the study, then the radiologist will only review that portion. They have already evaluated all the previous patients.
Thank you. That should reduce the risk of unwanted and unnecessary delays, I presume. Some follow-up on Oncoral, which is a very interesting proposition. Is there any prospect of if there will be any interim readout between 2022 and 2024?
At this point we would say we have not planned an interim readout. I mean, obviously we will follow the patients. We will do a dose escalation, and we will see what will be the dosing level, the exposure of the active metabolite. Then we'll move into the efficacy portion of the study. We're not planning on any interim data readouts.
Yes. If I understood it correctly, there are in the industry clinical studies actually combining LONSURF with standard of care IV irinotecan that will come out eventually. Is that something that could have relevance for your combination as well? Even though of course the proposition is to have completely different intervals with all the potential benefit that that could have. It's interesting. Well, earlier in this call you said that there only been preclinical combination, but we could actually have some results from clinical elsewhere in this combination. That could be interesting. Is that correct?
Yeah. We are aware of some clinical studies that have been initiated with intravenous irinotecan. What we believe is that this, the daily dosing have significant benefits. One thing is that when you have a monotherapy chemotherapeutic, side effects can be quite dramatic. When you combine two chemotherapeutic agents, which is often the case in clinical practice, then it's more difficult. This encouraging safety profile we saw in the phase I study, we think that will be a benefit. Maybe Andreas, you want to add something here?
No, I think you are pointing to the most important part here, and that is actually the oral and daily dosing. That has the potential to make a difference compared to the IV. But it's correct that there is data out there, or studies where they have investigated that combination of irinotecan and trifluridine, which is the active component of LONSURF. I think it's the important part for us is the all oral daily combo that has the potential to hopefully make the difference.
Also the fact that other people have studied this combination also points to the complementary mode of action that hopefully have a very strong effect on the patient treatment.
Excellent. Plenty to look forward to in 2022.
Absolutely. Yeah. Thank you, Johan.
Okay.
Thank you.
The next question comes from the line of Sten Westerberg from Analysguiden. Please go ahead.
Thank you, operator. Yes. If I may shortly briefly get back to this protocol amendment, since Orviglance is developed as a liver or kidney sparing agent, I mean, could you once again explain why you originally excluded the dialysis patients? That will be my first question. Second question, if your timeline for the study is depending or dependent on you reaching 50 recruiting sites or if this change in the protocol should help you get there before the end of the half year. Thank you.
Start with the latter one, whether patient recruitment is dependent on reaching 50 sites. I mean, as in all clinical studies, and especially within an orphan disease, it's huge variability in the, let me say, in how many patients each site recruit. Some sites have recruited zero patients to date. We are working with them to help them get going further. Some have been significantly more productive in recruiting patients. It's more, we're striking the balance between working with the sites that have figured out how to recruit patients and support them as much as possible.
Obviously for the ones that are less productive, we're doing a trade-off in terms of how closely are we working with them, how far are they from actually getting productive and getting patients into the study. The total number of sites is obviously important, but when we go beyond and look in the internal data here on the productivity between the sites, that's much more you would say important in terms of reaching the full recruitment. You should not see the total number of sites that have been opened up as necessarily a strong predictor for overall recruitment. On the first one, why did we initially exclude dialysis patients?
I would say that's a very good question, and one could argue in hindsight, we should have included them from the very beginning. We did that. We would say it's common to do in clinical practice because these patients are you would say the most sick patients, and that's why you would expect more complications. It's also in terms of the measurements because of the dialysis process where the blood is filtered by an external dialyzer, you would say measuring levels and all of those parameters gets more complicated. That's why we initially said we will not include these patients.
We will do some of them, a small subset to just validate the safety in dialysis patients as well, but not in the bulk of the study. What we're doing now is that we open up so that there's, say, no limit on dialysis patients in the study.
Okay. Yeah. I understand this trade-off between safety and recruitment. I mean, would you agree to that the risk or the risk level of the study is increased by including these dialysis patients?
No. Well, I don't think so. That's based on what we have learned so far. I think that's not. I don't see an increased risk in the study from this. It is more when we started out, there was a lot of things we didn't know. Now we've learned quite a bit. Inclusion here, we don't see that as adding to the risk profile.
Great. Thank you so much for responding to my questions.
Yeah. Thank you. Please.
As there are no further audio questions, I'll hand it back to the speakers.
Yes. Thank you, everybody, for listening in to our quarterly report presentation here. We are making good progress. We had, I think, a good news flow in the fourth quarter. We are working very hard on the key priorities and milestones here. We'll continue to update you on the progress that we're making. Thank you, everybody, and have a good day.
This concludes our conference call. Thank you all for attending. You may now disconnect your lines.