For those, Magnus, that have never heard about Ascelia, what do you do? How would you describe what you do in maybe just a couple of sentences?
Yeah, Ascelia Pharma is an emerging pharma company, a small pharma company, and we're developing new, new medicine, new drugs that help doctors treat rare cancer conditions. Cancer is like a multitude of different cancer types and subgroups, and there are lots of patients with cancer that have onset, or you could say not good enough treatment options. And we're working on that.
Mm-hmm. If we just zoom a little bit into which types of cancer do you work with, indications?
We have two products in our development pipeline, and the lead one is a imaging drug or diagnostic drug used when patients go into an MRI scan, magnetron in Swedish, when they need to look, when the doctors need to look at the liver to see if there's any cancer in the liver. Unfortunately, that's a very common problem in cancer care that it spreads to the liver, and therefore a lot of imaging procedures are being done every day. Our lead drug that has come very far in development, and we'll come to that, is sort of a first-in-class product that is very different from everything that is on the market today, because what is on the market today is based on a heavy metal gadolinium that is injected into the person going into the scanner.
In some patients, the ones where the kidney does not work well and have a difficult time getting rid of the gadolinium quickly enough, that can cause some potentially fatal side effects. All the products on the market today have this black box warning from the regulatory agency saying, for patients with severe renal disease, there is a risk for this potentially fatal side effect. Our product is based on manganese, which is a natural trace element. We all have manganese in our bodies, and we need small amounts of that. Therefore, we do not have that risk. Also, that gives us an orphan drug designation from the American health authorities, the FDA, that gives us certain benefits. We are sort of very differentiated, coming with manganese instead of the gadolinium that is being used today.
You're also quite differentiated when it comes to history of, of building of Ascelia. If we talk about, I mean, we talk about drug development quite a lot. We know which steps that have to be taken.
Yeah.
If you can walk our audience through which steps have been taken for Ascelia and what have you left in the journey of actually getting the drug to the market?
Yeah, you're right. The drug development process is very, very long, and it has been very long for us as well. We are almost at the end of the development phase. First you do your lab test and animal studies, and then you progress into human trials, phase one to test safety, phase two to test efficacy, and phase three to do sort of both efficacy and safety and in a statistical, compelling way. We have done to date nine different clinical studies. We completed the phase III study, Sparkle, had the results last year. That was a, you know, very strong outcome. We've then earlier this year had a meeting with the American Health Authorities. We've had many meetings with them over the years.
For at this meeting, we kind of put together everything we had, presented to them, and asked them some questions as you always do and got clarification. Based on that meeting, we said, yes, we're ready to submit. There goes a lot of work. We spend a lot of time finalizing the application. It's electronic these days, but back in the days when even when you had less data, you know, and they submitted binders to the FDA, it would be like two ship containers full of documents. It's a lot of material that you submit in this, and every single sentence needs to be right. It's a lot of work. We've done that.
Recently, just, you know, a couple of weeks ago, we got the day 74 letter, which means that the FDA has reviewed sort of high level the application, and they say this, it looks like you've covered everything and it, it looks good. There are no deficiencies that mean we will not review. Now they've kind of passed that gateway and go into sort of the full deep dive on everything, and so we're super excited about that. That's an important milestone. They also said that they expect to provide the approval around July 3rd next year.
Mm-hmm. You mentioned the date, the, the famous PDUFA date.
Yeah.
For the July. Can you give us some timing perspective? How long time has this taken and the drug development processes in general? It takes years to get to where you are.
Yeah, absolutely. Originally the company was, way, way back, was founded 25 years ago, but some periods it has not been, sort of very active. We started the phase 3 trial. We started that really in sort of end 2019, early 2020. That took quite some time to complete. When we think back about that timing, what is special is that we had the global pandemic coming just early 2020, which was a disaster for the study because all the hospitals said, you know, we need to focus on COVID and certainly not recruit patients for our trial. That took a long while and was a very challenging start. We persevered and came through and got the patients that we needed to demonstrate that it works really well.
Mm-hmm. If we zoom in a little bit on your lead product, Orviglance, from the, you know, you, we talked a little bit about the cancer population, the large amount of patients, but for Orviglance, what kind of patient population are we talking there? Which patients do you plan to treat?
Yeah, so the patients that could benefit from Orviglance is really all, everyone that have need for imaging of the liver. The most prevalent of that population would be patients with cancer, but it could also be patients that have other, you would say, diseases of the liver where it's important to do imaging. Liver, sort of cancer in the liver is the major problem. In the U.S. and in Europe, cancer in the liver is probably 90%, 90% cancer that starts in another organ. That could be the colon, it could be breast or lungs, and then it metastasizes, spreads to the liver. That's a very important sign for the doctors because they need to know if it spreads to the liver, it's a kind of almost like a different disease. It needs to be treated in a very different way.
Therefore, frequent imaging of the liver to see if it has spread to the liver, they need to, you could say, go to a different treatment paradigm and treat the patient in a very different way. That is why an accurate imaging procedure with a contrast agent like ours will help them see very small lesions. Sometimes we're talking about lesions that are in the millimeter scale that can be very tricky to see. What we saw in our phase III study was that we saw significantly more small lesions than an imaging procedure without any contrast. That was a result we were extremely pleased with, and also got a lot of, you would say, very positive feedback from the radiologists who participated in the study or have seen the study results.
Because earlier detection can mean a better chance of having a good treatment outcome for the patient.
Yeah. At the moment out in the clinics, what is, what do they use? You mentioned gadolinium. What is it?
Yeah. We are going for the small group of patients that is probably in the order of around 5% of everyone with cancer in the liver. That's 5% of them will have very significant kidney problems, and they are candidates for our product. We are not going after everything, but we are having what we believe is a very good product for these patients. I think that's what kind of sets us apart there with having a manganese option for these patients, patients that have a risk of potentially dying from getting a gadolinium injection. We've done a lot of market research to understand in the real world today, when these patients come into the hospital, how are they being treated? How are they being imaged?
We have a lot of data on that, and we've shared some of that, but I think one of the important takeaways is that we have market research supporting that for our patients, 60% of them will have an MRI without a contrast agent. Even though it's well accepted that that will give suboptimal images, there's a risk that they will not detect the cancer in due time. They may not be able to measure the size of the tumor accurately. That's important because when patients are in cancer therapy, they're getting chemotherapy or they're getting antibodies or other products, and the objective is to shrink the tumor. If you have blurry images and you can't see, you know, the exact size of the tumor, the doctor does not have the right tools to make the right choice.
Accurate imaging is very important. They need to make a decision for this patient coming in, let's say, every three months, and they look at the image, and if the patient is responding to the therapy, so the tumor is at least stable in size or it's shrinking, then they should continue. That's a lot of money for drug therapy for the next three months, and it's a lot of side effect. If the patient, if the drugs are not working, it's not attacking the tumor in a good way, they need to change to some different drugs. Again, the images and high quality, that's key for making those decisions.
Mm-hmm. Yes. The optionality of delaying or complicating treatment decisions is not good.
No. Especially because, typically when cancer has spread to the liver, or if we have the primary liver cancer that originates in the liver, that's typically a more advanced stage. If you are not making timely decisions, the prognosis for the patient is much worse. That's why it's so important to have the right quality image.
Maybe a very simple question, but, how do you take Orviglance? Because it's quite a difference. Gadolinium is intravenous and Orviglance is.
Yeah. No, so Orviglance is a powder, and it's put into a glass of water just roughly like this, 200 milliliter. Then the patient will drink it a couple of hours before the imaging procedure. Actually, for around four hours, we have a high level of manganese in the liver, and we can do an imaging procedure at any point in time there. Then it's excreted through the bile back into the gastric tract, which also means that we get almost no, none of the manganese goes into the blood circulation. That gives Orviglance a very unique safety profile because we are not, we don't wanna have the manganese in the, excess manganese in the blood circulation because of safety concerns. We don't see that. That's a big positive.
Whereas, as you say, the gadolinium, when you go into the scanning room, they will put in sort of a line and then they will inject the gadolinium. It goes into the blood, bloodstream and goes into, you could say, the entire body. That's also why, regardless of which imaging procedure you're undergoing, you get a similar dose, and you have enhancement of various tissues around in the body. Unfortunately, there's also deposition, which means that some of the gadolinium that is injected will stay in the body. That includes, you know, in particular the bone and the skin, but also the brain and other organs have some gadolinium deposition. Gadolinium is a heavy metal, so its deposition is not good.
It's put in a sort of a chemical structure to minimize the toxicity, but still deposition is not a good thing.
Yeah. Let's dig into the clinical data. You mentioned nine studies, but maybe we can concentrate on Sparkle, which is the latest study. What were you looking for in that study and what were the findings?
Yeah. The Sparkle study is sort of the phase III study that is designed to demonstrate statistically significant improvement of the visualization. Before going into a phase III study, which is a very large investment, we've had conversations with the American Health Authorities and the European Health Authorities to align with them. This is the study that we're planning, and getting feedback if it's successful, you know, would that support an approval? Obviously you never get any guarantees, but that's kind of the design was made based on their feedback and incorporating feedback that they had. What we had was 85 patients, where they both had an unenhanced, so they went into the MRI scanner without an imaging drug, and then with Orviglance.
They were comparing the different images before and after, and should compare when they saw something on the unenhanced, and then they should give it a score. Then with the enhanced, they should give the same lesion a score. You see it's a scale from one to four. If it's a two on the unenhanced, hopefully it's a higher one on the enhanced. That's what we demonstrated. We did have an issue with the initial evaluation where two out of the three readers had difficulties, you could say, consistently applying the one to four scale. We had to redo it, which was extremely unfortunate, but in the redo, we could improve the training. We could specify that in even further detail.
We didn't see this kind of, you could say, significant reading issue that was documented in the first go. Very compelling results. It showed for all three—we have three doctors looking at the image because it's known that there is variability. All three of them saw significantly better pictures in the way they scored with Orviglance, with our product, than without. We also saw, as mentioned, more lesions, especially the small lesions, which are more difficult to find. Again, a finding that is consistent with the earlier studies we've done, and also a logical one. If it's difficult to see something on an image, it's even more difficult to see the small millimeter size lesions. As expected, consistent with the previous studies and a very solid outcome.
That was also the data that we brought to the FDA when we had the pre-submission meeting and discussed submitting the application.
The FDA, the next important point to touch upon here. How would you characterize your communication with FDA so far?
I think we've had a good conversation and good dialogue with the FDA. Obviously, they have their set of, they have legislation that defined how they should act and they provide answers. I think our experience is that they've been very thoughtful and collaborative, and they also see a need for having something else than gadolinium on the market. We are the leading company in the world with an alternative to gadolinium. The first one with the manganese here. I think they appreciate that. I mean, they're getting feedback on the toxicity and safety side effects of the gadolinium product, and they publish that in a database. There continues to be reports of nephrogenic systemic fibrosis into that database every single year.
Not many, but there continues to be, and each of, and every one of them is one too many. For, I think overall, I think it's the right way to go. We have people who are sick or potentially sick, and they go for a scan to be evaluated if they're sick. We should not inject things into these people that can make them even more sick. Another element, which I think is also gaining a lot of attention, especially in Europe, but increasingly in the U.S., even though they're less focused on that, is the environmental aspect. With all the medical imaging that goes on, tons of gadolinium goes into the drinking water supply every year. That is documented in scientific literature where they take water samples, you know, going back decades.
When they measure the amount of gadolinium in drinking water, it goes up quite significantly. It's not a top three concern on drinking water quality. We have some more urgent concerns, but, you know, we look at the curves and at some point it's gonna increase. I think with the manganese, it's very different. Also, in case there should be too much manganese, it's at levels that are easily filtrated in our water systems already today. I think overall in terms of this concern on the environment, but also on the gadolinium deposition in every person who has an injection, it is creating a shift in the mindset of radiologists.
Also, even now, the large manufacturers of gadolinium are increasingly seeing we need to limit the level and the doses of gadolinium. They are working on that. Some of them are also being more explicit about we need to find alternatives to gadolinium. Obviously, that is a drug development process, as you know, is a long process. I think they are definitely taking steps in that direction. We are super happy to be the first with a new manganese agent.
Yeah. We have a question from the audience there.
Yes. What if you have done a comparison between your products and gadolinium regarding visualizing of pathology? This is the first question. The second is the same comparison, but regarding the side effects between gadolinium and your product, especially allergies and anaphylactic reactions. Then, what kind of product is, substance is your, in your product that you mean it's, it's favorable, environmentally?
Yeah. The first one, comparison with gadolinium, in the phase III study that we performed, we compared Orviglance to an unenhanced MRI. That was what we had agreed with the authorities. Really considering the patient population where there's a black box warning from the gadolinium product, it would be unethical to do a study where we inject gadolinium in them. That's the comparator. We have done earlier, some years back, at the Karolinska University Hospital here in Stockholm. We did a study in patients with normal kidney function. They both had a gadolinium agent and they had our agent, and unenhanced.
In those 20 patients, when we did a sort of a thorough reader setup with three independent readers, which is kind of the qualitative way to, the high quality way to do that, we saw statistically significant improvement with Orviglance than the unenhanced. Very strong results only in 20 patients. When we did the comparison with the gadolinium agent in 20 patients, we had higher scores, depending on the parameter on visualization or lesion detection than the gadolinium agent. That difference was not statistically significant in 20 patients. It's very difficult to show a difference in a statistical manner. What we say is that when we look at the parameters that are important for the visualization and detection, we are at least as good as the gadolinium.
We don't, I think it would require, you know, a massive study in size to have any statistical difference between those two agents. The anecdotal feedback we get from the investigators who participated in our trials is that the image quality with Orviglance is very high and they like to use it. I think that's, you know, one thing is the data. I think also the subjective experience from the radiologist is important. The point is that they are not, you know, when you look at the liver with an MRI agent, we can provide a high quality image with Orviglance, and we don't have any of the gadolinium associated risks that the patients that we target covered by the orphan drug designation from the FDA, they are the most vulnerable and sensitive for this risk.
That is the positioning that we have. Sorry, the second question was again.
Unexpected, yeah. After using, you know.
Yeah.
I'll just.
Regard to the safe for, for gadolinium.
Yeah.
Including those nephrotoxicity.
Yeah.
We'll just repeat the questions for the live. The second follow-up question was on the side effects and the nephrotoxicity and maybe some allergies as well.
Yeah. For our, what we have seen in our clinical studies have been consistent throughout the development. Typically the way it works is that we have patients who, they will be fasting all morning, they will come to the hospital, they will drink a glass of water with our powder in it. Then they will be measured for any potential safety signals. What we've seen is some gastrointestinal, which really means that, you know, they can have a bit of nausea. They can have a bit of mild diarrhea. All of this is mostly mild and very transient and over with a few cases of vomiting we've seen. I would say in this very sick patient population that's expected.
Remember that many of these patients have a health standard that is, you know, they are on chemotherapy and in poor condition. The feedback we get is that, you know, this is perfectly acceptable in terms of, you would say, the severity of the disease. What we also, we have not seen any serious drug-related side effects in our studies. It's a really, you would say, I think it's really important to note, no anaphylactic shock. You would not expect that because manganese is a natural trace element. It's something that all of us have in our bodies. We also have alanine and vitamin D in our formulation to improve the absorption in the small intestine, and that would also be, you know, it's something we have in our body.
That would also, you know, make anaphylactic shock extremely unlikely, I would say. When we think about the gadolinium agents, I mean, there are packaging search for all of them, and I can't speak to that, but obviously the risk for nephrogenic systemic fibrosis, this risk in that is most, that's highest in patients with renal disease, is obviously well established with the black box warning. There are also cases of acute nephrotoxicity. So, acute kidney injury or in rare cases. We have not obviously seen any of that in our studies. We would not expect that because what we have demonstrated is that in the studies, when the patient drinks the Orviglance, it goes to the liver, but most of it passes straight through the colon.
When it gets to the liver, there's something called a first pass effect. The liver protects us from excessive uptake of whatever, and especially for manganese, and then it goes straight back into the gastric tract. The manganese does not go into the blood circulation. We measure the blood levels after dosing at a number of different time points, and they mostly stay within sort of the normal range, almost all data points. It gives us a very unique safety profile for this product. We could also see that we did a study at the Texas Liver Institute where we took patients where the liver is dysfunctional. Sometimes when you have a significant liver disease, the liver function is really bad.
It may be more porous and it may be, and we also saw a very good safety profile there. We also saw that it does not, the manganese does not go into the urine, which means that it does not go through the kidneys. Again, a very important safety measure for our product.
We are beginning to run out of time here. Before we have the closing remarks, potentially an approval from FDA, and to commercialize, I imagine you will not be taking on that task on your own. What's the strategy there? Are you talking to partners already?
Yeah, absolutely. Our strategy, I mean, we're a small company. We're 10 people in Malmö. We're working with partners around the world. We have manufacturing in the U.S. We don't have the scale to build up a commercial infrastructure in the U.S. or in other geographies. Our strategy is to partner, to find a pharma company that already has the infrastructure in place and that will be effective in commercializing to bring this to the patients. We have done a lot of work in terms of understanding the market, understanding the reimbursement system and how Orviglance could be reimbursed and used in clinical practice in the U.S. We have a lot of data on which hospitals see the most of these patients, where to go, et cetera.
That is something that we'll be sharing with the partner. We have an ongoing process of finding a new partner. We are in various dialogues and it's always interesting. I think it's, you know, we're very happy with the recent milestone that we had with the FDA where they said, you know, the application looks good so far. We continue our full review. I think that's always helpful. Sometimes, you could say there's arguments for doing, you know, a deal sooner than there's clarity on who the partner is. On the other hand, you would say if we do it a little bit later, we've come further and we created more value.
I think the milestone we just had is an important milestone for some partners. I think as we progress and approach the approval timeline, we'll continue to create value on the asset. I'm very comfortable with the experienced team that we have in driving this process. We have some very trusted and experienced advisors helping us in this process, and dialogue with the FDA. I'm very optimistic that we'll get a good outcome. We get the drug on the market and get a partner in place so that the drug can go out and help the patients who need it.
If you would say just one short key message to our clients here and everyone listening online, what would you like people to remember about Ascelia? What is the key investment point here?
Yeah, I think the key point is that Ascelia is, you know, despite we're a small company, we are gonna be the first company in the world with a, a liver specific manganese agent. We are gonna have a product that for this patient population will, will be sort of the, should be the product of choice because it has good efficacy, it has good safety in a very fragile patient population that have very poor opportunities today. They are the patients that, that we will help, and serve. We have come very far. We've invested a lot of time and money into bringing it to this stage. Now we are, approaching the, the final phases of, of the approval review process. You know, I'm, I'm super excited about it. The team is, is super excited about it.
We have, you know, come so far. So we're very excited and looking forward to, to the coming period.
We are looking forward to following you on that journey. Thank you very much, Magnus. Thank you all for listening in.
Thank you.