Welcome to the Isofol Medical Audiocast with Teleconference Quarter One 2022. Throughout the call, all participants will be in listen-only mode, and afterwards, there will be a question-and-answer session. Today, I'm pleased to present CEO Ulf Jungnelius and CFO Gustaf Albèrt. Please begin your meeting.
Thank you so much, and good morning and welcome to Isofol's presentation of our first quarter results. It's a pleasure for us to report on the excellent progress that we have made during the last couple of months, allowing us to at last start the unblinding process that will result in us being able to communicate top-line and kind of data results from the pivotal AGENT study. Next slide. The disclaimer, this is not a prospectus. If we go to slide number three, today's presentation is myself, Ulf Jungnelius, the CEO, and with me I have Gustaf Albèrt, our financial officer. Why is Isofol a blockbuster? If you go to page number four, a blockbuster investment opportunity.
Keep in mind that colorectal cancer is the second deadliest and the third most common form of cancer, with an estimated increase of a fantastic 60% over the next 20 years. A high unmet medical need area. Arfolitixorin has the potential to be the first novel drug for all comers with metastatic colorectal cancer in almost 20 years. Arfolitixorin is expected to target an addressable market of approximately $1 billion in peak sales. We have a late-stage, fully recruited phase III pivotal study, and we have started the data analysis process. Isofol has two strategic license agreements in Japan with Solasia, in Canada with Paladin Labs, at a value of $123 million.
Isofol has secured a robust IP protection in the U.S. and Japan to 2038 and in the rest of the world to 2034, and we are working on to prolong that. Isofol has a strong financial position, and it has been listed on the Nasdaq Stockholm mid-cap segment since October 2021. We go now to slide number five. What are the highlights from our quarter report from the first quarter? We have had a close and frequent dialogue with the FDA with the goal of obtaining the FDA's approval of the AGENT study updated statistical analysis plan. We're planning for a Pre-MAA meeting scheduled in the second half of this year. We also started the clinical preparation to ensure proper collection and thorough analysis of AGENT study data once we have that.
We are planning for upcoming scenarios and associated go-to-market strategy based on the information gathered during 2021 and during the first quarter. Productive conversations with new and potential partners are ongoing, strengthening our U.S.-based activities for increasing the awareness around arfolitixorin by public relations and communications and medical affairs. I'll come back to that. If you go to the next slide, the planned pre-commercial activities are now being executed, and we're making real good progress. Our goal is to achieve a value-creative business development discussion platform and to prepare for a successful commercial launch as early as 2023. What we have done is we have our second medical team member, MSL, on the ground. We have updated the medical narrative. We are expanding our MSL team force. We're preparing for ASCO and BIO International.
If we look on the market side, we have updated market and payer analysis, market research demand. We're looking at mapping out the patient journey throughout the treatment. If you look on communication, we have completed a US-based communication and agency commission, and we're in progress of basically doing the strategy and positioning of our communication within the group. A lot of things have happened, and we are pursuing a number of things that we will report in the second quarter report. If we go to slide number 7, this is a high-level update on the AGENT study. Isofol has begun the readout and analysis of AGENT study data. This is a very complex process, and it will lead to the unblinding of the database. Eventually, we can extract the top-line data and the final results.
The discussions following with the FDA on the censoring rule and the number of progression-free events required to start gathering resulted in us being able to do this now in the end of April. Of course, we will have a discussion with the FDA once we submit the NDA and they have reviewed the package. Analysis of the study will be based on 490 patients, which means we have also included the Japanese patients. It will be analyzed with both the original censoring rule, but also the newly approved FDA censoring rule. This will be included once we submit the new drug application. The integrity of the AGENT study database is essential and it remains strong.
Isofol is firmly focused on a comprehensive analysis, and it expects it will take up to two-four months from the start of the analysis before we have the top-line results. We will then of course communicate that. A little bit about the phase III study. The primary objective, just to remind you, is overall response rate. That's the percentage of patients who experienced a tumor reduction according to the RECIST criteria. This is looked at with both MRI and CT scan. The secondary objective of importance for us is progression-free survival, and that is the time until the tumor starts to grow again. These two endpoints are very important when making a clinical decision, and of course for regulatory agencies to see that the drug really has benefit compared to the safety side.
We're working hard on that. It's on to page eight. On page eight. Yeah, sorry. As you know, we have not seen any safety issues throughout the study. If you look a little bit on the study design, as you know, it's a very in phase III terms, a simple design. We're basically comparing FOLFOX6 with Avastin with arfolitixorin-FOLFOX6 with Avastin. The only difference between the two arms is that we're in the standard arm using leucovorin, and we have replaced leucovorin with arfolitixorin in the experimental arm. The minimal acceptable results that are the regulatory threshold is of course that if you look on the label, the study's done in first line metastatic colorectal cancer, and it is with 5-FU combination.
Our objective response rates from what the FDA and EU may have told us is that we need to show at least a 10% improvement over standard of care. If you look on the progression-free survival, we're looking at trying to aim for more than 1.8 months improvement. Of course, we don't want to have an excessive toxicity, so the benefit risk ratio should remain at least the same, if not better. If we go to slide number 9, what are the next steps? Top-line data, of course, is the first glance at the key endpoint from the clinical study. Then we're looking at the duration between top-line and final data. We will have additional data included when we are aiming for the final data. The current data we have will mature.
Quality assurance and more in-depth analysis are included, including, for example, that we will also be able to present the data on the gene expression analysis in the final data. The final data is much more comprehensive and detailed. The study then is complete, and we will go into a hard lock of the database. Based on that data, we will decide if it's enough to submit for an NDA. Of course, also going to congresses and the peer review journals with the data will be important. If you look on the colorectal cancer market, it's again a large underserved patient population. Nearly 2 million people are diagnosed with colorectal cancer every year. Those with metastatic disease, only 10% live longer than five years.
As I said earlier, there is a 60% increase expected in the next 20 years of the incidence. This is a really critical issue for oncologists and healthcare providers around the world, as there has been no new drugs for the majority of the patients, the all-comer patients. If you go to slide number 11, the high unmet need in metastatic colorectal cancer, and as I pointed out, there hasn't been any new drugs for the all-comer population, which basically means that all major guidelines recommend the use of 5-FU based treatment together with Opdivo in colorectal cancer and mandated in the first line of treatment of metastatic colorectal cancer.
This will continue for the foreseeable future. Most new targeted agents, for example, the PD-1 inhibitors and the BRAF inhibitors, are only appropriate for a small fraction of the metastatic colorectal cancer population. With the BRAF inhibitors less than 10% and the PD-1 inhibitors less than 4% are eligible for that type of treatment. If you look overall, 90% of patients are welcome. There are also only a few drugs currently being developed for the first-line treatment, and most of them are old drugs or a combination with radiation therapy. This market segment is without competition or branded drugs. It's a fantastic business opportunity. Saying that, I will now hand over to my Chief Financial Officer, Gustaf Albèrt, on page 12.
Thank you, Ulf. Please turn to page 12. Financial overview, Q1. We continue to receive reimbursement for the AGENT study in Japan, and that will continue during into 2022. Operating costs have increased compared to same period last year. Costs for the ongoing AGENT study related to patient enrollment, et cetera, is decreasing over time. All the costs for preparation for compiling the study results and later on NDA filing and preparation for all those things are increasing over time. Costs related to pre-commercialization activities, as Ulf outlined, is also increasing over time related to different activities performed. Costs for staff are increasing due to two more FTEs compared to last year in the same period. Costs in overall are in line with our plans. Please turn to page 13.
Cash flow from operations for this period is in line in all material aspects to the operating results. All in all, we have a good cost control, and we are well-financed, as Ulf mentioned, and with a strong position, financial position to execute the planned activities outlined by Ulf and related to the completion of the AGENT study and filing of the NDA and the pre-commercialization activities that are being executed and will be executed going along the way. Now over to you, Ulf, and our strategic prioritization. Please turn to page 14.
Thank you, Gustaf. Let's focus on our strategic priorities. First of all, focus on a diligent, efficient, and high-quality approach to analyzing the data that will lead hopefully to an NDA submission to the FDA. We want to continue to execute on our strategic partnerships in Japan and in Canada and pursue dialogues with additional potential partners, licensors. We're also looking strategically to evaluate go-to-market opportunities. Keep in mind, depending on what the data looks like, there will be different scenarios on how to take the drug to the market. The fourth strategic priority is building Isofol's awareness and value through accelerated pre-commercialization activity. If you look on the upcoming milestones, we're expecting the top-line results coming in the next two-four months, three months.
We are looking at the primary efficacy endpoint, where we will probably have 100% of the data in the database, and also have a glance at the secondary endpoint, where we will not have complete data yet as the data is coming in and maturing. If you look at the potential application, that will happen in the second half of 2022, which means that if you go to the approval process, that will take roughly a year. Here is where we can have help of the Fast Track designation to shave off time, which puts us at a potential approval by the end of 2023 with a launch soon thereafter.
If we go to the next slide, which will be the last slide before the question and answering, I will review with you our investor highlights as I see this as a unique opportunity for a novel drug in metastatic colorectal cancer. Firstly, there is no branded competition in key markets where 5-FU-based regimens are dominant. Late-stage truly recruited phase III study is in-house with the data being analyzed as we speak. Isofol has a phase I/IIa study that demonstrated an impressive efficacy in a small subset of patients with no safety issue, and this is the backbone to our clinical study. Keep in mind also in that study, we also had data not only with oxaliplatin but also with irinotecan, and this will be important, and I can mention that later.
Isofol has taken a more structured approach to protecting their IP compared to other companies, and we have patents now valid until 2038, and we're working to get that to be worldwide. Strategic CMC partnerships with Merck and Sai and Recipharm are in place since a long time back, 2013. A strategic licensing agreement with Solasia in Japan and Paladin Labs in Canada since 2020. Our pre-commercialization activity has been initiated, including the development of medical affairs and commercial launch packages. As I mentioned, we now have two medical liaisons on the ground in the U.S., and they are working with key opinion leaders, thought leaders, increasing the awareness around the drug and will be present at ASCO now in Chicago in a couple of weeks. Isofol is aiming for a launch in the U.S. market as early as 2023.
This is again, as I said, supported by the Fast Track designation that we got in the beginning of the year. I will finish my presentation here and go back to our moderator for questions. Back to you, moderator.
Thank you. Ladies and gentlemen, we will now begin our question-and-answer session. For those who are dialed in through the audio line, if you would like to ask a question, please press zero followed by one on your telephone keypad and wait for your name to be announced. If you'd like to cancel your request, that's zero two. Again, for those on the audio line, that's zero one on your telephone keypad now. Your first question is from Peter Ostling. He's from Pareto Securities. Your line is now open, Peter. Please go ahead.
Yes. Thank you for taking my question. I have quite a long list, but I will start off with a couple of ones and then jump back into the queue. You say that you use a little bit of rephrasing in the report compared to previously. You say that the top-line data will provide an indication on the results. What kind of evolution do you expect from the top-line results to when you have the final results? That's my first question.
Okay. Thank you, Peter. This is a very important question. When you have top-line results from a study, that is just a large subset of the total database. As I mentioned in my presentation here, I gather we would have probably 100% of the primary objective data, the response rate data at the top line. That would be something we feel comfortable with. When it comes to time to event data, patients are still being followed up. We have patients that have not had a progression, which means that we will have more data coming in from the time we soft locked the database for the top line, until we actually have the final database. When we look at the top-line results, they may be indicative.
Here you can see basically if everything goes like I pray for, the data with the confidence interval may look really strong. If we have a smaller subset, the denominator will be smaller, and thus the confidence interval around the time to events will be much larger, which means that we will perhaps have to wait until we have the final data to be more secure on where we are going with that data set. I hope that helped you.
Yes. Yes, sure. Yeah. Thank you. Then you also have started to talk about a little bit around different scenarios that.
Mm-hmm.
You see will pan out, that could pan out from the study. I was just wondering if you could elaborate a little bit on the main scenarios here and how that would affect your future plans for commercialization.
Of course, when you have a Phase III study which is blinded, you have basically no clue what's going on in it. I take the two most extreme scenarios. The one extreme would be that we don't meet any of the primary endpoints in the study, then we have a failed study. That's one extreme. Then you don't have a go-to-market strategy, of course. The other extreme is that the results are so fantastic, so basically, you don't need to wait for the final unblinding. That's an easy one. There is your fantastic commercial opportunity. Everyone is satisfied except payers. You have a number of in-between scenarios. We can play with one scenario. Your response rate is just on the border, but your progression-free survival is significant.
How does FDA look at that? We have a number of those scenarios. The other thing is, as FDA allowed us to submit both, the data with the old censoring rules and the new censoring rule, what happens if you have a difference between those packages? Again, these are the things that we are considering and trying to understand how that would impact a commercial business case.
As I understand it, all scenarios implies that you at least reach the 10 percentage points improvement in ORR.
Yes.
There is no go-to-market plan if you only reach 8%, for instance.
Well, that would be the one extreme where we say we reach 8%, but we have a statistically significant progression-free survival.
Okay.
I would say that then the FDA would scratch their heads and wonder what to do. I would say that's an outlier. The ones we are looking at are, of course, that we reach the primary objective and then different ways of looking at the progression-free survival results.
Okay. In your discussions with the FDA here during the spring, have you discussed these different scenarios?
No.
with them how they
They're not interested in that.
Okay.
Keep in mind that the FDA is only interested in the data, not the consequence of the data from a commercial perspective.
Okay. My final question before I jump back into the queue, have you gathered any new info on why more patients than expected proceeded to other treatments and how that could jeopardize the secondary endpoints of PFS?
No, we have not. Keep in mind, we're still blinded. When you start the unblinding analysis process, it's in the very late stage of this process, after a couple of months perhaps or a month or so, that you actually unblind the study. What's going on right now is to complete the sampling of the data, doing the quality control of the data, and then also the quality assurance of the data. Once that is done, we can break the blinding, but that comes very late in the process. The time between breaking the data and doing the statistical analysis is rather short. It's left to the clinical team to draw conclusions of what the statisticians have come up with.
The longest time here is actually getting the data into the database in a quality assured way. That's the majority of time.
Okay. That's what you mean when you say that a comprehensive and proactive effort has been made.
Yeah.
during Q1 in order to facilitate a smooth and quality assured readout process. That's what you're talking about there.
Yeah. That's correct.
Some of that work already started while you had these discussions.
We could start some of the collection of data prior to the FDA decision. The quality assurance and stuff, that's going on right now.
Okay, great. Thank you, Ulf.
Thank you.
I jump into the queue.
Thank you, Peter. Your next question is from Christian Bender from Redeye. Your line is now open. Please go ahead.
Hi, and thank you so much for taking my question. Just one from my side. You mentioned that you're continuing existing dialogue with potential partners, that you've also initiated some new dialogues. I wondered whether you could just give a little bit more color regarding the general sentiment among potential partners. Are they relatively eager to strike a deal, for example, after top line data? Or, do you think they're a little bit more hesitant and may want to wait for example, final data?
I'll take that answer in two sections. First of all, there is a very, very high interest in our product, Isofol right now. We have a number of companies knocking on our door. Of course, the next step they wanna take is after we actually have data. Everyone tries to minimize risk. Everyone, I would say, with common sense is waiting for the actual top-line data to appear before they make any decisions. We've had people in our due diligence database. There are a number of levels in the due diligence database. Going through, for example, all the public information that we have already shared with people, et cetera, right? Everyone is very careful.
We are waiting for data, like everyone else, and so are they. The interest is there. We have basically interest from all geographies right now.
All right. Got it. That was all from my side. Thank you so much.
Thank you. Your next question is a follow-up question from Peter. Peter, your line is now open. Please go ahead.
Okay, thank you. Let's see here. Just some brief ones. When you say, do you have any specific data when you say that you expect the number of colorectal cancer cases to increase by 60%? I guess that's all colorectal cancer, not just for the metastatic part.
No. Yeah.
Since there are a number of broad new screening programs in place. I guess the metastatic part will grow significantly lower than the 60%.
The incidence figures for colorectal cancer are taken from the WHO and other large organizations. There's a clear trend, and we have had discussions with different countries, like Japan, incidence is much higher than in Europe, for example. We had discussions with China, and they shared the data with us. Surprisingly, the incidence increase is much higher than we anticipated. With the screening programs and keep that sort of a Western way approach now, it hasn't been implemented everywhere. The incidence will increase slowly. One reason is the aging population, but also, in the US, for example, it's associated with lower socioeconomic groups, right?
There are different reasons why you see an increase in it, but it's truly a statistically significant increase of high magnitude that's going on.
Yeah. Okay, when you have talked to payers, how do they value the different endpoints in the AGENT study, response rate, PFS and overall survival? How important is it that, for instance, the improvement in PFS also is statistically significant and not just as a positive trend?
No. Good question. There is a clear difference between geographies. Basically, I would say in Europe, payers want overall survival. The problem we've had or the challenge we've had is to educate payers around the first-line setting in metastatic colorectal cancer. Payers are not well educated when it comes to different cancers. There is the belief then that, yes, you should come with overall survival, and it should be very long. The reality of first-line colorectal cancer is not obvious. Of course, when we say, you know, that our primary objective in the study is the response rate, a number of them just are confused, I would say.
Until you educate them and say, you know, there is a reason why FDA and EMA were adamant that we should have objective response rate as the primary objective. So it has taken some education from our side, but in the U.S., it has been significantly easier to get the message across to payers. In Europe, it's been more difficult. We'll see about Japan. Keep in mind, the study with regulators have been approved worldwide, and payers in Europe, different countries are very different from each other in Europe as well. Of course, everyone wants to see a prolonged overall survival or a prolonged progression-free survival. That's for sure. This is why the secondary endpoint is important for us. Over to you.
Yeah. From now until you present the top-line results, will there be a complete silence, or will you announce in any way when you open the database for analysis so that the real countdown could begin?
No, I don't think we will do a PR when we open up the database. Basically, it's a non-event in one way because when you break the blind, it's just a part of a working process where you now allow statisticians to actually look at the data in both arms. The tangible results of the analysis is the first-line data that will be communicated one way or another.
Okay.
It won't be silent. I'll tell you. I'll be there and talk to you.
Good. You now say that you believe that, being that you need to conduct additional clinical trials in order to establish what genes specifically will be relevant for to look at as a prognostic tool. What kinds of trials do you foresee? Is this the same kind of magnitude as the AGENT trial or some smaller ones?
If I take a step back, when we went to the agency in 2017, I think it was, or 2016, they were adamant that we needed a validated commercial kit when we analyzed the gene expression data. We now have a validated commercial kit. In the final analysis, we will have done that analysis on the gene expression on all patients. The results is that experimental endpoint, exploratory endpoint in the study. Basically what the agency said is you cannot use this for an indication in the label, and that's okay. It actually validates the hypothesis.
The next step is that if this is true, that say now 70% of patients don't really metabolize leucovorin in a way that they actually have a clinical benefit of it becomes from a regulatory standpoint a little bit of a regulatory ethical issue to continue to recommend leucovorin in metastatic colorectal cancer. What we need to do is again to show that this gene expression has implications in other cancers where 5-FU and leucovorin are basically baseline drugs. Take for example, pancreatic cancer, breast cancer, head and neck cancer, esophageal cancer. The intention there would then be to do smaller studies because now we know the magnitude of the impact on leucovorin versus arfolitixorin in the form of efficacy and safety, right?
A study design would be looking at the significantly higher difference between the two arms. It doesn't necessarily have to be a randomized study. I think it would be enough that we demonstrate high efficacy based on gene expression. The gene expression in our study, it would not be a companion diagnostic. This is a validated hypothesis that we will do with this study. Then taking it forward, if we do it or if someone else does it for us, will be the next step to add additional indications, sNDA to the label.
The data that you compile within the AGENT study using this commercial kit will be good enough to be used with colorectal cancer but.
No, what I said is it won't be in the label, right? Because it's an exploratory endpoint. What I said was that the regulatory agencies have not made it easy for themselves if the hypothesis holds true in a large randomized study that the
That, that's a discussion point with the authorities, you mean?
Yeah.
Yeah.
I don't think we will discuss this because it's an internal discussion within the regulatory agency. If the control arm is not effective and one of the drugs in the control arm has no activity in 70% or more of patients.
Mm-hmm
Can you continue to recommend that drug for those patients?
Yeah. Yeah, I hear what you're saying.
And-
Thank you.
Now we have an alternative, right?
Yes.
Mm-hmm.
Great. That's just finally just a housekeeping question. The reimbursement that you get from the Japanese part of the study, will that continue throughout 2022, or will it be just another couple of quarters where we see this SEK 4 million or SEK 5 million in income?
Dr. Gustaf Albèrt, over to you.
It will continue for the rest of 2022.
Okay. With approximately the same kind of magnitude of income?
It will decrease over time, along with the patients ruling out of the study.
Okay
in this nearly the same magnitude.
Okay, great. Thank you. That's all for me.
Thank you. There are currently no more questions in queue. I'd like to hand over the call to our moderator to go through the web questions. Moderator, please go ahead.
Yeah, all the questions coming in from the web has been answered already during the Q&A session. Those are answered. Great. Thank you.
No worries. Once again, ladies and gentlemen, if you would like to ask a question, please press zero one on your telephone keypad and wait for your name to be announced. We will pause for a moment to build up the queue. There are currently no more questions in queue. I'd like to hand the call over back to our CEO and CFO for their closing remarks. Please continue, gentlemen.
Thank you so much, and thanks for all your help. Again, the AGENT study is in a holding pattern waiting for the top line and final result. As I said before, we expect these results to come in during the summer, probably when all of us are on vacation. This will then be announced when we have the top-line results. That will be a key communication from Isofol. We are working strongly to increase the awareness of our arfolitixorin in the U.S. market, which is the first market we're aiming for. We now have two MSLs, medical scientific liaisons, on the ground in the U.S., and we're expanding that, the field force.
We have also contracted communications professionals in the U.S., so our focus now is to really increase awareness and also getting the messaging in order for a potential launch already in 2023. Things are going really well. This quarter has been really full of things we've been able to execute on, and we are in a financial really good stage. No dire straits during the terrible times we're going through right now. I expect to have another meeting with you in a quarter with the Q2. Thank you so much from Isofol. Over to you.
Thank you. Ladies and gentlemen, this concludes our conference for today. Thank you all for your participation. You may all now disconnect.
Thank you. Bye.