Good morning, ladies and gentlemen. Welcome to our Q4 and Full Year 2020 Highlights and Financials. My name is Jan H. Egberts, I'm chairman of the board. I'm here together with Lars Nieba, our interim CEO, Malene Brøndberg, our CFO, and Marco Renoldi, our COO. Over the past year, I've acted somewhat as an executive chairman, spent quite a bit of time with the company. Also, my colleague board members have worked very intensely over the past year. First of all, I want to acknowledge this has been a very difficult year and a somewhat disappointing year for all of you and all our shareholders, since our stock price has not performed at all over the past year. Unfortunately, we had to spend that year focusing on a number of very important operational fixes, which unfortunately resulted that we had very little news to report.
I'm very pleased that I think today we can report some very positive news to you, and I know you have been waiting for a long time for that. The next presentation that Lars and Malene and Marco will share with you will show you that we have now more than doubled our recruitment rate from about roughly 12 patients during the first three quarters in 2020, so over the period of nine months, 12 patients, to 14 patients over the most recent three months. Up over the first three quarters of last year, about three per quarter to 14 over the most recent three months. That's the period from mid-November to mid-February. A very significant improvement in our recruitment rate.
This all in spite of the fact that today we're still in the middle of a second wave of the COVID-19 epidemic, which had a huge impact on the ability of running non-COVID-related clinical studies. Real hospitals were locked down and were closed for those kind of initiatives. I'm also very pleased to report that we were able to reduce the number of required patients for submission due to the protocol changes that we have implemented during 2020. Now we only have 47 patients to go to completion of PARADIGME, so a significant reduction. We also expect that this recruitment rate will further improve to about eight patients per month or so in the late spring, early summer of this year.
Some of those further improvements in the recruitment rate to the eight I just mentioned will come both from ongoing operational improvements, but also from lessening of the corona impact after the second wave, which we expect will abate during the summer, but also more and more people getting vaccinated. A further significant increase in our recruitment rates. Just to refresh your memory, pretty much exactly one year ago, we embarked on a very major organizational refocusing. We appointed Lars as our interim CEO, Malene Brøndberg as our new CFO, and later in the year, Christina as our Chief Medical Officer. In addition, very early on last year, we made a number of very significant operational changes. Significantly reduced operating costs, reduced our headcount by 25%, which really extended our runway.
Unfortunately, in that process of reducing the headcount by 25%, we had to let go some of our excellent people. In addition, we also revisited our clinical protocol. Based on the interim analysis that we conducted in the middle of the year and that we released in early August, the external independent safety monitoring team recommended that we should drop one of the two arms of our PARADIGME study. Until halfway last year, if you remember, we had two arms, and now we have only one arm. The reason for this is, given the great safety profile, the monitoring board felt that we should take the best-performing arm and that because of the safety profile, we should be able to lift some of the restrictions we had on our clinical protocol.
From that moment on, we were able to include patients with lower platelet counts, but also patients who have had bone marrow transplantation. These two facts, the lower platelet count and the patients that were coming included with bone marrow transplantation, who have had bone marrow transplantation in the past, will increase the number of eligible patients we could potentially include in our clinical study by, depending on the country, depending on the local practices in the different country, anywhere from about 30%-70% more patients that could be included in the clinical study. A very important addition that would make more patients eligible for the clinical study. After that decision, these also need to get approved by the local regulatory authorities. As of this month, we just completed that entire process of getting all the local regulatory authorities to approve these protocol changes.
In addition, with the help of Karin Meyer, one of our board members, we implemented a significantly improved management of our CRO, our clinical research organization. We also implement improved patient recruitment tools, in particular in the U.S. A number of additional measurements and decisions that really will help us improve our recruitment. In summary, I think we're very positive where we are. We have only 47 patients to go to complete the PARADIGME study. Our recruitment rate has increased from about three per quarter during the past year to 14 patients over the most recent three months. That all in spite of the fact that we're still in the middle of a very significant second wave of COVID-19. Like I mentioned earlier, we expect our recruitment rate to increase even further to around eight patients per month in the late spring, early summer.
In short, we reiterate and repeat our guidance of our key value inflection point of three months data readout in the latter part of this year. Probably the question you will ask, why did it take so long? Because of the nature of biotech and the fact that Betalutin treats very sick patients, any change you'd like to make to a protocol, like dropping one arm or broadening inclusion criteria, takes a long time to implement because you do need regulatory approval in each of the countries where you're operating the clinical study. Again, we fully realize that 2020 has been a very difficult year for our shareholders, but we're really optimistic where we are and that we really have changed a corner now and can leave the phase where we need to implement all the required operational and organizational changes to fix our recruitment rate.
Now we can focus on the more exciting phase of the submission and towards the market launch. We're not at the submission yet, obviously. We need to complete the clinical study. We definitely feel that the operational changes have now all been implemented. I really want to acknowledge all the hard work that has been done by the team, particularly Lars, our Interim CEO, Malene, our CFO, Marco, our COO, Christine, and the rest of the management team. Also really there's a lot of operational support from the board, particularly people like the Chair of our Clinical Strategy Committee, Jean-Pierre Bizzari, together with Johanna Holldack and Rainer Böhm. They have been very intimately involved in all the drafting of the protocol changes and some of the discussions with our regulatory authorities. Also, Karin Meyer was very instrumental in the improved management of our CRO.
Hilde, as Chair of our Audit Committee with Per and myself, have been very intimately involved in the financing. I think that our new CMO, Christine Wilkinson, summarized it best a couple of weeks ago during a team meeting when she said, and I quote her, "We're beginning to see an encouraging improvement in the enrollment rate of PARADIGME. Based on the changes of the trial protocol and the initiatives that we are implementing to improve the execution of the trial." This is where the important section is. "We now have clarity from the key regulators on the clinical data set that is expected as a basis for our filing.
This clarity, in conjunction with improving enrollment rate and the continuing recruitment initiatives, gives us confidence that we can meet our goal of having preliminary three-month top-line data in the second half of this year. Really, we feel very confident we're now on our track to have the three months data by the end of this year. This has been a true team effort, working with management and the board, working hand in glove. That's kind of what I want to summarize. I now would like to hand over to Lars, who will take you through the rest of the presentation. Marlene and Marco.
Thank you, Jan. From my side, good morning, everyone. As Jan mentioned, let me go with you in more detail through our Q4 update. I will start with the most important update on PARADIGME. As Jan mentioned, we have made a significant improvement to our recruitment rate. We have accelerated our recruitment rate from approximately two to five patients per month despite COVID. Also we are expecting that COVID is lessening. As soon as that happens, the rate can further increase to at least seven patients on average per month in late spring. Where did that improved rates come from? We have significantly improved the management of our CRO and also retained specialized firms to further improve our recruitment. We have converted our PARADIGME trial from a two-arm into a single-arm trial. We also introduced simplification in the execution for our clinicians.
We have a very good positive safety data set from the interim analysis, and that also allowed us to broaden our inclusion criteria. We are now able to include patients with lower platelet counts and also after autologous stem cell transplantation. That pool of eligible patients increased, depending by country, between 30% and 50%. The analysis of interim data showed that number of patients to complete PARADIGME can be reduced. We were able to present that to the health authorities, and we can reduce the number of patients to 120, and that means we only have to have another 47 patients to go to finalize PARADIGME for the regulatory submission. With all of that, we reiterate our target to report preliminary three-month top-line data in the second half of this year. Let me go in more detail through the highlights. We have now 73 patients enrolled as of yesterday.
To remind everyone, we had 59 patients as of November 18th. That means we have 14 patients enrolled in the last three months. We had only three patients from August to November 2020. There you can see that all of our actions really come to fruition, and we are very confident that we can even go higher. Our protocol amendments have now been implemented in all 24 countries. Last ones, we're approving it last week. The final patient has been enrolled in our second cohort for ARCHER-1, our second-line Betalutin trial, and also in the LYMRIT 37-05 phase, where we are treating DLBCL patients. Preliminary data readout is expected in the first half of this year. Both trials now have been paused pending the analysis of data and the evaluation of further plans and development.
We also were able to publish in The Journal of Nuclear Medicine the results of our preclinical studies demonstrating that Betalutin reverses tumor resistance to rituximab in non-Hodgkin lymphoma disease models. All of that is really very, very positive, and we are on the right track. Reminding everyone what Betalutin is. We're going to slide seven. Betalutin has a compelling, unique, and differentiated value proposition for non-Hodgkin lymphoma patients. As a short reminder, we have an anti-CD37 antibody. CD37 is highly expressed on B-cells. We do have lutetium with a half-life of seven days as an active compound, and the mechanism of action of our antibody-radionuclide-conjugate is internalization and cell death, and very important, the crossfire effect of lutetium, which gives us really very, very good results. The key benefit, especially during the pandemic, we should not forget our elderly patients.
We only have a single-dose treatment. None of our competitors has that. We have a durable response in elderly and heavily pretreated patients. Our safety profile is very good. We have a predictable and manageable side effect burden. Very importantly, most of the treatments today are anti-CD20 treatments, and we do have an alternative target to CD20, which is suitable for rituximab-refractory patients. Now, as we promised, when I took over in February, that we wanted to revise our clinical strategy and that we are focusing on PARADIGME. That is what really happened over the last year. We brought forward PARADIGME, and PARADIGME is our first-to-market trial. The indication is third-line relapse/refractory follicular lymphoma. We are, of course, together with the data out of ARCHER-1 and LYMRIT 37-05, which I mentioned, they're finalized, and we are analyzing the data.
We are looking with all of that data together to really evaluate the optimal strategy to advance in earlier lines. Since we do have also pretty good results in marginal zone lymphoma, we are also looking on the opportunity how to move ahead with marginal zone lymphoma. Going shortly to Part A. Sorry for everybody who has heard that several times. I think it's still a very impressive story. What you can see here on the waterfall diagram is the amount of shrinkage of the tumor size. What you can see there in our 74 patients, which we had in the 37-01 Part A trial, that about 90% of the patients had a shrinkage or reducing in tumor size. Slightly other description is that we have an overall response rate of 67%, and 24% of CR in rituximab-refractory patients.
As I mentioned, these are really the ones which were suffering most from not having any therapy available. Our median response rate for all responders is more than a year, and even more than two and a half years we do have for our complete responders. That's really a very impressive result with progression-free survival of around nine months. That is also important for how we position Betalutin in the market. As Jan mentioned, we are now preparing it. I would like to remind everyone our patient characteristics is that we have elderly patients. The median is 68 years old. There is no huge difference between Part A and Part B. They've been heavily pre-treated with advanced stage disease, and that is also pretty similar between Part A and Part B. Overall, we have a very good safety data set and efficacy data set in that patient population.
Betalutin is very well-tolerated. That is why we also can now treat patients with lower platelets and autologous stem cell transplantation. The interim analysis, as mentioned by Jan, we had it in July last year. We had before a two-arm trial with a lower dose and a higher dose. The lower dose was the 15 megabecquerel per kilogram Betalutin and the pre-treatment of the cold antibody with 40 milligrams flat of lilotomab. The higher dose arm was 20 megabecquerel per kg Betalutin and 100 mg per meter squared lilotomab. These were the two arms, and the Safety Review Committee looked at all of the data in very much detail and recommended to go ahead with the 40/15 arm. As mentioned, we have 73 patients enrolled as of yesterday, and the trial is 220 patients with 47 patients to go.
We have 95 sites open in 24 countries. We have promised that our number one priority since I took over is the improving of trial execution. Let me recap a little bit what we have done. The protocol amendment has been mentioned already, is now approved in all 24 countries. The broadening of the inclusion criteria has increased the pool size by 30%-50%, depending on the country. The decision to make PARADIGME a single-arm trial led to the reduction in patient numbers needed to complete PARADIGME for BLA filing. 47 patients are now needed to finalize it. The site-specific action plan has been implemented. Senior leadership at Nano and our CRO are deeply involved in continuous monitoring the site performance metrics, which are also increasing significantly. CMO is hosting virtual meetings with trial investigators and the teams to promote PARADIGME. Christine is very active here.
She had more or less every PI on the call, and they are appreciating that very much. The specialist firms we have appointed are there to focus on further improving our rate of recruitment, including targeted social media campaigns. The major focus currently is North America, and there in particular, the U.S. There's also some other facts from our competitors. The three trials of our competitors have been finalized, and one bispecific antibody trial is on clinical hold. That also might give us a few additional patients. Very important also here is the vaccination rollout is expected to reduce restrictions imposed on COVID-19. As you know, our patients are on average 68 years old. They are in the group which needs to be protected. From that point, it is very important for our patient population that the vaccination is going on very fast.
Our regulatory strategy to gain rapid approval. BLA filing with the FDA for accelerated approval based on PARADIGME data in addition of confirmatory phase III trial. That is important. We will go ahead with our phase II-B PARADIGME trial. We do have Orphan Drug Designation for third-line follicular lymphoma granted in the U.S. and the EU. We do have Fast Track granted for both follicular lymphoma and marginal zone. In the U.K., we do have also the Promising Innovative Medicine status. Of course, we are always exploring other routes to bring Betalutin faster to our patients. Now, coming to the positioning of Betalutin. Going to slide 16. What you can see here is what we mentioned before as well.
It is a unique product profile of Betalutin which positions us as a treatment of choice for elderly and frail patients, which are approximately 70% of all third-line follicular lymphoma patients. If you progress at a very early stage into third line, you have great medicines like the stem cell transplantation, which I mentioned, or also the CAR T, which is close to approval, as they are looking with very promising results. They are expensive. They do have high side effects, and only a very few patients are eligible for the CAR T therapy. Bispecific antibodies also having promising results. Do have very high side effects, which we can see on the clinical hold of the Regeneron bispecific antibody. Going further to the elderly and frail patients in the green circle here. If you are looking around that, there is not a lot out there for our patient population.
We do have the old REVLIMID, we do have rituximab, and rituximab refractory is not very effective. We do have PI3K inhibitors, three of the first generation and one of the second generation has been approved. Their side effects are very high, they are rarely used. We do have a competitor with tazemetostat. Good results, only in a very minor fraction of patients who do have a certain mutation which corresponds to approximately 15% of the overall patients in follicular lymphoma. Overall, that means there is still a high unmet need. With our safety profile, with our single injection, we are very well-positioned to serve these patient populations. Patients who have comorbidities that prevent the use of both chemotherapies or other therapies associated with a high side burden, they are very well-positioned for Betalutin.
What we have shown is a durable response with a very good safety profile in the single administration, as mentioned. Really very well-positioned for that. That is also the feedback we are getting more and more from our customers is the efficacy observed in 37-01 is seen as a major strength. Our response rate and the median duration of response and complete responsiveness is very compelling to hem-oncs. The combination of potential benefits is what sets Betalutin apart. The one-time treatment, the durable efficacy, the manageable and benign safety profile, and the simplicity for patients and physicians. Hem-oncs, your elderly and frail patients, which are the majority of the patients with follicular lymphoma, with comorbidities, including patients with refractory to rituximab, as the ideal Betalutin patients. With that, I will hand over to you, Malene.
Thank you very much. Let's take a look at the financials. As you can see, we have still a good control over the finances. We spent NOK 107 in the last quarter, which is compared to NOK 139 last year. Of course, we see here some of the effects of the reduction we did in unfortunately staff, but other things as well earlier or in 2020. As you can see also, we will continue to, of course, to look for further savings. When that's said, we do not, of course, want to jeopardize the study. We do want to complete on time. It is most important now to spend the money on the right thing, which means, of course, clinical and also our CMC activities.
On the next slide here, you can just see that the cash runway, which is now extended into a Q3 2021, so this year. It gave us, in the end of the year, a cash position of NOK 294. As we will continue, as I said, to look for savings so we can push it as far as we can. As I said, NOK 294 in the bank in the end of the year, in the end of the quarter, which is, of course, a result of the financing round that we did in September. With that, Lars, I will hand it back to you.
Thank you, Malene. We are 100% focused on delivering on our PARADIGME trial. We are highly confident in the potential of Betalutin to fulfill the important unmet clinical needs. The goal is to complete PARADIGME, and we are targeting our preliminary three-month top-line data in the second half of this year. We have reduced the trial size, and that means we only have to have 47 patients to go to complete PARADIGME for BLA filing. We have significantly improved the rate of patient recruitment into PARADIGME despite the second wave of the corona pandemic. Our inclusion criteria have been broadened. We have shown that we have a very good safety profile, and we are even going further with additional initiatives to further enhance the rate of recruitment. Our promising clinical efficacy and safety data seen from our one-time administration in relapsed/refractory follicular lymphoma.
Very important to mention is Betalutin is a 100% owned asset. We are targeting a total [audio distortion] opportunity to approximately $26 billion by 2026. Of course, we are actively pursuing flexible regional commercialization strategies to maximize our value. With that, I only need to remind everybody on the next dates from the financial calendar. The AGM will take place on the 15th of April. You will hear our Q1 results end of May on the 26th. The first half, the half-year results on the 27th of August. With that, we are open for questions.
Yes, good morning. We do have quite a lot of questions here, but many of them are similar. We're trying to address the main questions here now. First question is about financing. We have a couple of questions here related to the future financing plan. Referring to in the Q3 report, you said something about the extended cash runway could be done with different tools. How will the company work looking forward to secure the financial situation from Q3 2021 and forward?
Jan, will you take that question?
Yeah. As we mentioned during our previous quarterly, we do need to raise some money during the first half of this year. We clearly want to raise money beyond what we consider the key value inflection point, which is the three-month data readout later this year. Management, together with the board, are evaluating various options. We will hear more about in the nearby future. It's clearly a recognition, which we mentioned during the previous quarter release, that we need to raise money at some stage during the first half of this year.
Thank you, Jan. We do have a lot of questions about the PARADIGME study, of course, and some of them have been addressed and answered during the presentation, but some of them are also new. First one, what is the impact of COVID-19 on follow-up visits and data collection for PARADIGME?
A very good question. What we are doing is, as mentioned, we have really very good interaction with our CRO and also with our investigators in the hospitals. The overall processes are now in that way that we always have somebody in the hospital who can take care of that. Wherever a visit is possible, of course, we are doing the visit. When not, we have implemented procedures that are corona conform, and that we can get all of the data and most of the visits made as mentioned in the protocol.
Thank you, Lars. The second question about PARADIGME is on recruitment. Can you indicate anything on the geographical split of where most patients have been recruited from so far?
Far, as we mentioned before, our best recruiting countries have been historically the U.K. and France. What we are seeing now is that wherever the Corona pandemic is going down, we do see a huge impact on the patients are coming back. From that point, we are expecting as soon as the Corona is going down, that also all of the other countries will come back.
Thank you. There is also a question about the split between the 40/15 dose and the 100/20 dose among the 37 patients that have been recruited so far.
The 37 patients?
No, sorry. The 73 patients.
Yes, of course. There was a split because we have until the interim analysis, we went ahead with the two arms. We have done the interim analysis at 47 patients. As soon as we got the approval for the single arm, we have focused on the 40/15 trial. The patients which have been dosed with 100/20 are of course, counting to the overall patient number of the 120.
Thank you. Sorry, that question disappeared right now. Do you see any safety issues with regards to the patients treated under the new protocol?
No. We don't see anything there yet. We need to be careful here because we, of course, need to wait for the three-month data of the patients. As mentioned, the protocol has been approved in now all 24 countries, and we have patients coming in under the new protocol. We have not reached yet the three-month data set.
We have not had any material adverse changes.
No.
That would have been reportable, just to be clear.
Yes.
There are no material adverse changes at all. It has a very strong safety profile, the compound. There are patients with comorbidity, which means they have multiple other diseases. We're dealing with very sick patients. We have not seen any indication of any problems with the compound itself.
Okay. Next question is could you comment further on the target for the three-month top-line data in second half of 2021 with respect to when you then would need to be fully recruited, and what rate of enrollment would be required to reach this?
What we mentioned, we are very confident that we can reach our preliminary three-month top-line data this year. As mentioned in the presentation, we are very confident that we can increase our rate of recruitment to at least seven patients per month.
Thank you. There is another question about MZL and whether it's possible to provide an update regarding MZL.
Yeah. The update is that, of course, we are working together with our Clinical Strategy Committee, with the board on how can we move ahead. As Jan mentioned in his introduction, that is also a strategic question. We are looking on where do we position the company best, and we have very good results in marginal zone. We are working on a clinical protocol there. As soon as we know more, we will inform you.
Thank you. Could you also say something about Alpha37, how that is going?
That one was only very minor presentation yet. We have put our research activities on hold. We are looking as soon as we do have a clear path forward there that we might want to go ahead. Yet, as mentioned before, we focus everything on PARADIGME, and with that, we have put it on hold.
Thank you. We do also have some questions about regulatory approval and market access. There's a question about where we do stand when it comes to the Fast Tracks.
Fast Track is a regulatory status. As soon as we have submitted, then the FDA is agreeing to handle that with the Fast Track pathway. From that point, we are still having, of course, Fast Track, but since we haven't submitted yet, there is no Fast Track pathway yet. We expect as soon as we have the data that we are reaching out to the health authorities so that we can have the submission in 2022.
You mentioned both FDA interactions and internal review provides you confidence that 120 patients is enough for a filing for accelerated approval. The question is, did the FDA approval that 120 patients number? What color can you give on what gives you confidence?
As we mentioned before, we have regular interactions with the health authorities, and we did get very good feedback and interactions with the health authorities, and that is why we are absolutely confident that the 120 patients is good for submission. Of course, depending on the clinical data.
Thank you. Another question is there a minimal amount of U.S. patients specifically that you need to recruit to support an FDA filing?
There is no specific requirement for U.S. patients. There's no rule or any law or something like that in the FDA regulations. It is more that there is, of course, an expectation that you have to have some U.S. patients, as we have seen with our competing trials. We are in a good range there that we are confident that we reach sufficient U.S. patients, to meet the expectations of the FDA.
Yeah. The other thing to keep in mind is that the FDA is now accepting also patients from countries that you kind of have a mutual recognition. Not just the United States, but also some other Anglo-Saxon countries.
Thank you. The next question is can you file in Europe based on PARADIGME, or is that unlikely?
Marco, in that case, I need to hand over to you. I think you have looked into that in very much detail on our European approach.
I think in general European regulatory authorities have been a bit more rigid in terms of approving products based on phase II-B trials. Most recently, drugs that have demonstrated a strong clinical advantage over available therapies have been able to obtain conditional approval. Our first priority is, of course, filing with the FDA, but we will explore all options to support a filing with the EMA authorities as well with the current trial. I hope that satisfies the question.
Thank you, Marco. We are going to raise the last question here, and after that, there might still be some questions that have not been answered yet, but the more detailed questions will be handled by email in order to not go in too much detail here. The last question is about partnerships. The usual questions. Are there any big pharma companies that are interested in making a deal with you, or have you been contacted by big pharma? Are you thinking about such cooperations?
Sure. We are always thinking it is our duty to the company. We are always investigating different business development opportunities and, as usual, we will revert to you and to markets with updates if and when any of these discussions materialize.
Thank you, Lars. That concludes the Q&A session. As I said, there might be some questions that have not been answered yet of the more detailed kind, and we are going to respond to those by email. Thank you.
Thank you, Kari. Thank you, everyone. With that, I think we can conclude session. Jan, anything from your side? Final words?
Again, I want to thank everybody. I want to acknowledge that last year has been a very difficult year for our shareholders, but I really think the company has now turned the corner, and we're now really at the phase of moving forward towards the submission of Betalutin and going to the market. I think we are entering a very exciting phase, and both board and management are very optimistic about the future. I want to thank you all for your support over the past year. Again, I acknowledge it was not an easy year, but I think we're going to the finish line now.