Good morning. My name is Martin Olin. I'm the CEO of BerGenBio, and today with me I have Cristina Oliva, our Chief Medical Officer. We will give you an update on the Q4 2023 report, with some post-period updates on our main focus, the first-line non-small cell lung cancer STK11 study. I will just remind the audience about the formalities. In a nutshell or highlights, BerGenBio's fourth quarter represented a very interesting momentum in the operations but also in our financial performance. Our main focus is the first-line STK11 non-small cell lung cancer study, BGBC016, and it's really progressing as planned. There are no new safety signals observed as of today.
We have received regulatory approvals in all six countries that we have selected in the European Union, enabling the initiation of the phase II-A sites, in the first half of this year, as we have also previously guided. We have seen a very strong support from the oncology community, which makes us really encouraged about the ability to progress the study and complete the enrollment. The focus strategy has significantly reduced our operating expenses. For the 2023 financial year, operating expenses totaled NOK 192.2 million, which represent a reduction of 37% compared to the operational expenses, for 2022, which stood at NOK 306 million. The year-end cash position of NOK 156.4 million are projected to fund our operations until the end of 2024, in line with previous guidance.
If exercised all the outstanding warrants that can be exercised in the first two weeks of April this year, we'll extend our runway into the second half of 2025. We're also gratified that bemcentinib data that we have reported continues to attract significant interest, and we have reported multiple p hase II data in prestigious oncology meetings throughout 2023 and also in the fourth quarter of last year. Most recently we have announced that new preclinical data continues to support the potential of bemcentinib beyond non-small cell lung cancer, or we should probably say beyond oncology. This is the focus of the company: first-line STK11 non-small cell lung cancer, which, by all means represents a significant opportunity from a lot of aspects.
If we look at lung cancer today, it is still by far the largest cause of cancer-related death, and non-small cell lung cancer represents roughly 80% of lung cancer incidences. Despite the advancement in the treatment of non-small cell lung cancer, the unmet medical need remains significant, and it is particularly related to two levels. One, those patients who either have a negative or low expression of PD-L1 are known not to respond well to checkpoint inhibition in combination with chemotherapy, which is the standard of care for these patients. But in addition to this, the disease or the treatment of the disease is complicated by the fact that there are a number of non-targetable oncogenic mutations, of which the largest one, or one of the largest one, STK11 represents up to 20% of front-line non-small cell lung cancer patients.
This translates into a very significant opportunity, if measured at today's pricing, of drugs, for the treatment that will be beneficial for the patients. We believe that this represents a market opportunity in the US and the EU5 in Europe of more than $4 billion annually. If we look at the STK11 and the acceptance of the fact that it is a poor prognostic factor, the STK11 mutation and the impact, or the medical impact, has certainly gained increased attraction and has been reported, in numerous prestigious journals to be a bad prognostic factor. And in that respect, I think we can say that BerGenBio's role, or bemcentinib's role, as an AXL inhibitor, actually has gained significant interest, as a potential modality to address a rather complex biology related to the STK11 mutation, which Cristina will address, later on in the presentation.
We do believe that the aspects or the features of bemcentinib, a highly differentiated AXL inhibitor, have some very nice potent features, which makes it ideal as an immunomodulatory agent in combination with checkpoint inhibition and chemotherapy in front-line therapy that we are currently pursuing. First of all, it's a highly selective, potent, and improved inhibition with fewer side effects. It concentrates in the lung by a 40-fold over normal tissue, but it also crosses the blood-brain barrier. Both of these are really interesting features in the treatment of a lung-related disease, in this case non-small cell lung cancer. We have a very extensive database. We have studied the drug in more than 600 patients and have shown that it combines very well with chemotherapy and checkpoint inhibition. It's safe, and we have also seen monotherapy activity in a number of indications.
We have received a Fast Track designation from the FDA for this particular subset of patients. Why is this relevant? The relevance of a Fast Track designation opens the opportunity to have a closer interaction, more frequent interaction, with the FDA or the regulatory agencies in the United States to resolve issues and also enable a faster process towards a potential approval for market authorization. We have recently filed, or in the last 2 years, filed IP that protects bemcentinib in this particular indication until 2042. I will now hand over to Cristina to walk you through the case of AXL inhibition in non-small cell lung cancer.
Thank you, Martin. Good morning, everyone. Over the next few slides, I would like to walk you through the case of the AXL inhibition with bemcentinib in first-line STK11 mutated non-small cell lung cancer. AXL expression on tumor cells, but also on immune cells, plays a critical role for the disease progression and metastatic spread. AXL expression on tumor cells actually activates a series of signaling pathways that lead to survival, proliferation, migration, angiogenesis, therapeutic resistance, and immune evasion. But AXL expression is also very relevant in the host cells, and specifically in immune cells, creating a tumor microenvironment which is significantly immunosuppressed. Bemcentinib inhibition of AXL is expected actually to play a role both on tumor cells and on the immune microenvironment. Bemcentinib has demonstrated to add clinical benefit to patients treated in combination either with chemotherapy or checkpoint inhibitor.
We believe that actually treating these patients early, meaning in first line, before they actually develop therapeutic resistance, may significantly delay their disease progression and hopefully prolong their survival. But what is actually the environment that is created by an STK11 mutation? STK11 mutations create an immune desert with AXL expression and also drive the immune evasion. Therefore, a tumor which is an STK11-deficient tumor develops a significantly immunosuppressive structure, what we call actually a cold environment which is refractory to immunotherapy and has very specific characteristics. Number one, a striking infiltration of immunosuppressive cells that you will see at the bottom in blue, including the Treg but also the TAN, which are actually tumor-associated neutrophils.
On the other end, it also creates and induces an exclusion of most of the inflammatory immune cells that are depicted here in red, and just to name a few of them: the CD8 T cell, the NK, the CD4 T cell, but also the M1, the macrophage type 1. All in all, this creates an environment that does not respond to therapies. What is relevant for our case is that AXL actually is expressed in the vast majority of STK11 mutated non-small cell lung cancer, and it actually substantiates what is the detrimental role of AXL in creating an immunosuppressive environment. Therefore, targeting AXL, on one end, could restore the response to immune therapy in STK11 mutated patients, and we know that STK11 mutated patients do not respond well to immunotherapy, but on the other end could also reduce the resistance to chemotherapeutics.
So STK11 mutation is definitely an attractive target, but it's not an easy target to be identified or to be treated, I should say. Why? Because it has a very complex biology. A study has recently reported that on the STK11 gene there are over 1,300 mutations. The vast majority of the STK11 mutation, over 80%, result in a loss of the STK11 expression, making therefore drug targeting really challenging. Therefore, the best and most promising approach in this patient population that is currently underserved by the therapeutics available is to improve their immune response. Let me walk you through some preliminary new clinical data. You might recall that actually we have reported preclinical data supporting the mechanism of action of bemcentinib in immune cells.
This is a new observation that we are currently expanding to other subjects, and it's a patient case study out of our BGBC008 second-line study. You might recall this was a study, a phase II, conducted with the combination of bemcentinib and pembrolizumab in patients previously treated, and the aim was really to observe clinical benefit in this patient population with a pretty bad prognosis. In these specific cases, we observed not only a clinical benefit offered by the combination, as this patient, as you can see in the third bullet point, had an overall survival that goes beyond 16 months in second line, but also has allowed us a first assessment of the immune cell status that was evaluated pre and post the first cycle of chemotherapy.
The preliminary observations seem to support the mechanism of action of bemcentinib, and specifically that, number one, the cells that we know are critical to induce an immune response to cancer are indeed activated following the treatment with bemcentinib and pembrolizumab. On the other end, the immunosuppressive cells, like the Treg cells that actually are kind of negatively impacting the response to cancer, result as being decreased in number. And another very relevant observation is that actually we have now evidence of AXL inhibition and of target engagement from bemcentinib. This study will be further increased in terms of numbers, so we will definitely report additional data at a later stage. So we are not the only one targeting STK11 mutation, but we are actually reassured that our approach to target the immune response in this poor prognostic patient population actually seems to be validated by other clinical trials.
As you can see here, there are some trials ongoing that target not just STK11 but other poor prognostic subgroups of non-small cell lung cancer. We believe that our key differentiator is that we are the only one actually targeting AXL, and I hope actually I have explained to you the biological relevance of AXL in this patient population. We are supported by the data we have gathered so far in a relevant indication, which was a second-line non-small cell lung cancer, and we believe that these data definitely support the potential for adding benefit in first-line STK11 mutated non-small cell lung cancer with a combination of checkpoint inhibitor and chemotherapy. So let's just remind ourselves what were the main data: the encouraging progression-free survival and overall survival that we have observed in approximately 100 patients previously pretreated.
You see that actually the PFS positively compares with the available comparator in this line of therapy. The overall population benefited from the treatment, but what's interesting is actually that patients with high AXL had an even better and longer benefit. Results: positive results have been observed across the population regardless of the PD-L1 status, and preliminary data show that actually there is a potential benefit also in hard-to-treat mutations that are characterized by an immunosuppressive environment, like not just STK11 but KRAS and KEAP1. Let me give you an update on our first-line study. I want to remind you that it's made of two phases: the phase I-B, which is a run-in phase where we will study the combination of bemcentinib, checkpoint inhibitor, and chemotherapy, so the standard approach in this subset of patients.
The I-B is progressing per plan, and as Martin has just mentioned, no new safety signals have been identified to date. The phase II-A will be exactly the same regimen, but it will be applied to a selected group of patients with STK11 mutation. It will be a global study conducted both in the U.S. and in Europe. We have selected high-volume oncology centers with high expertise in the treatment of non-small cell lung cancer. We have obtained the competent authorities' approval for all the countries that we have selected to participate, and we definitely see strong interest and a very active participation from our investigators that clearly will try to identify a new treatment in a high unmet medical need that is represented by patients with this poor prognostic biomarker STK11. So what are the key expected newsflows?
Number one is the start of the phase II-A, expected in the first half of this year, and then of the interim analysis in the second part of 2024 and in the first part of 2025. So in summary, to conclude this case of AXL inhibition by bemcentinib in this patient population represented by first-line STK11 mutant non-small cell lung cancer, there is across the medical community an increase about the awareness of a need for new treatments in this patient population. As I said, this is a patient population that is significant in number but actually is underserved by the current therapeutic options. Extensive AXL expression in STK11 mutated patients is actually reflecting an immunosuppressed microenvironment. AXL expression is also relevant when it is identified on immune cells, as I showed you, and on tumor cells, creating actually a cold system that poorly responds to available therapies.
We have early evidence, and we are broadening this evidence as we speak, of the immune activation that is induced by bemcentinib and that supports bemcentinib's mechanism of action. We have previously reported efficacy of bemcentinib when combined with either chemotherapy or checkpoint inhibitor in two phase II studies that have been reported and presented at various conferences or submitted and accepted as manuscript in second-line non-small cell lung cancer. We have observed activity of bemcentinib as monotherapy in difficult-to-treat patients. Therefore, we really believe that offering an early intervention in first-line STK11 mutated non-small cell lung cancer would have the ability to reduce and delay the tumor chemotherapeutic resistance, therefore to provide a better clinical efficacy to these patients that are in high need of a new treatment.
As I mentioned, the ongoing study, BGBC016, is progressing in accordance with the guidance we provided that would allow for the initiation of the first two phase II-A in the first half of 2024. Let me now switch gears and share with you new data that supports the role of bemcentinib in serious respiratory infection. These data have been recently presented, just really a few days ago, at the Respiratory Tract Infection Conference in the U.K. and have actually demonstrated that bemcentinib has activity in human in vitro models of infections that are caused by different viruses like influenza, respiratory syncytial virus, and rhinovirus. In this model, it has been observed that bemcentinib actually reduces and downregulates the two cytokines IL-6 and IL-8, that are two important inflammatory cytokines that are associated with the severity of the disease.
On the other end, in another model actually of influenza, bemcentinib has demonstrated actually to control or limit the lung damage that is induced by the infection, therefore supporting tumor tissue, sorry, healing and repair. This is something that has already been reported from our ACCORD study , where actually the addition of bemcentinib to the standard of care reduced the cytokines, again IL-6 and IL-8, that are both associated with COVID-19 disease. And as you can see, the addition of bemcentinib to the standard of care for COVID-19 has demonstrated actually the ability to shorten the hospitalization in these patients or to prevent the further deterioration of these patients that were in a very frail condition. And I would like now to hand it over to Martin to go through the key financials and the newsflow. Thank you, Cristina.
This slide represents a summary of the key financials for the fourth quarter of 2023, and as you can see from the slide, the focus strategy has continued to show a reduction in the operating losses, which stood at NOK 43 million for the quarter, and importantly, the net cash flow was reduced to NOK 11.8 million in this quarter. We expect a stable cash use in the period going forward of around NOK 40 million per quarter, and that we believe will enable us to go to the end of 2024 based on a cash position of NOK 156 million by the end of 2023.
Importantly, the warrant exercise or the warrants that were issued in relation to the rights issue we completed in the summer of 2023 may have exercised allow the company to continue its operations, primarily with the focus on the first-line Non-Small Cell Lung Cancer STK11 study, into the second half of 2025 and potentially unlock some very significant value potential related to the data from the 2016 study. This is a snapshot of the key newsflow that we expect for the remainder of 2024.
So for the first-line STK11 Non-Small Cell Lung Cancer study, we are still in progress, and we plan to complete the phase I-B enrollment as previously guided, and also therefore to initiate the phase II-A study both in the U.S. and in Europe, as Cristina alluded to previously, and also importantly, I think, to continue to analyze the PBMC mechanistic data related to the mechanism of action of bemcentinib in those patients that were treated in the 008 study. I think we've also made some significant advancement in the establishment of a synthetic control arm, which will, of course, not replace the randomization principle, but it will certainly, give weight to the data we hope to generate, in this study.
In the second half of 2024, we are planning to announce some interim data from the I-B/II-A study, but we also continue to seek for opportunities to publish our data, and in this case could be additional PBMC MOA data in the second half of 2024. Other relevant newsflow is, of course, the warrant exercise period, the outcome of it. The period is the first two weeks of April this year. We're going to represent, or present additional severe respiratory infection data, and we may also be able to announce potentially new clinical trials focused on lung cancer, and funded by third parties.
We expect to have an update on the partnered program, with ADC Therapeutics, namely the program that is named ADCT-601, and in the second half of this year, an update on the tilvestamab outlicensing process, but also, manuscripts from completed studies we expect to be published. So in summary, we believe that BerGenBio has a very clear focus with the approach in first-line STK11 non-small cell lung cancer, with some encouraging development, the phase I-B enrollment, and the completion of the phase II-A in line with the guidance, the interim data, which may potentially unlock significant value, which is based on the fact that there is no available effective treatment for these patients today. We believe that BerGenBio is certainly on the frontier of exploring a treatment modality for this patient population.
Our cash position allows us to fund our operations to the end of this year, but the warrant exercise in the first two weeks of April may actually support our runway into the second half of 2025 and allow for additional data related to the first-line non-small cell lung cancer study. That was today's presentation. Thank you very much for listening, and I think we will have a Q&A session. Yeah, we have some questions from the audience. So, can you update on the enrollment of the STK11 study and the different doses? Yes, we can.
So as I have said, probably numerous times before, we are not giving specific guidance as to the number of patients in the study, but we are progressing in line with the guidance, which means that we would expect to be able to initiate the phase II-A study in the first half of this year. And importantly, we have seen no new safety signals, which is the primary endpoint of the run-in study, the phase I-B part. Thank you. Cristina, do you have any? Oh, I think you covered it very well. Thank you. Do you see any competition from patient enrollment from other clinical trials at the sites you have included in the trial? Cristina? Yes. There are definitely competitor studies. I have mentioned just a few of them, but we are not actually seeing any competition at the site level. What happens when you run these clinical trials?
Actually, you take a commitment, and the investigators at the site make a commitment not actually to accept any other studies that would be in the same indication or in the same patient population. So the competition is very active, which is actually, for us, confirmation of the value of the STK11 proposition, but no competition at a site level. Of clinical trials and treatment, so are there any comparable, alternative treatment methods in the market for the non-small cell lung cancer, and are there any competitors, from other companies to combat this indication? So you've seen, actually, we have just selected a few of the competing studies. They have all different combinatorial approaches.
What's common across the board is that actually they all aim at stimulating the immune system, but the mechanism of action is slightly different, and as I said, bemcentinib is the only AXL inhibitor that actually is currently in clinical trial for this STK11 indication.
Can you share any insight or early data from the STK11 study, or when would this be available?
So we expect to provide initial data from the study in the second half of 2024, as we have also guided previously. Although we have, of course, it's not a blinded study, so we have some insights, but the number of patients are in reality at this moment in time too small to make any valid conclusions.
I think we can say that we are very encouraged by the progress and also the fact that we have at this point seen no new side effects, and that's the most important part because that allows us to open the II-A study, which is the efficacy assessment part of the study. You mentioned the E.U. approval for the phase II part of the study, but do you have a U.S. approval?
Yeah, yeah, yes. A long time ago, yes. What is left to start the phase II part of the study?
That is to confirm the selection of the two doses that we have identified in the phase I-B part. Correct.
So we will move into the phase II-A only once we have actually identified the dose, and that's actually the reason of completing a run-in phase, to have a clear understanding of the safety of this combination and the best dose to move into the expansion in II-A. Yes. You mentioned the newsflow, but can you give the key milestone during 2024 and when we can expect this to take place?
So I think it's obvious that there is at least one very key milestone in the first part of 2024, which is the initiation of the II-A study, which I think, Cristina, by all means, is a major milestone because we would then have cleared the safety part.
And in the second part, equally important and probably even equally exciting, the initial first interim data from a small, though not the full population, but for a relevant number of patients being treated in the first II-A part. So the question about partnering: why doesn't you have a partner yet, and when can we expect one? I think if you think about where we are in the development of bemcentinib, we have now established a clear focus in first-line non-small cell lung cancer for a particular subset, which are patients with an STK11 mutation. And there are two elements to consider here. First of all, we have not yet established the safety profile. We are doing that now. We believe that we are progressing it very well.
But also, STK11 mutated patients are, from a clinical point of view, a relatively new discovery, and therefore I think we should expect, which we have also said previously, that a partnering event is most likely more relevant when we have both safety but also initial and potentially mature safe efficacy data from the study. But if delivered to what we can hope for, i.e., if we can repeat what we have seen previously, we are very encouraged by the opportunity to eventually find a partner, which we also, by the way, think may actually be the best route forward for bemcentinib to reach the market as fast as possible together with a partner, but later on. A question about the cash going forward: will the cash burn increase in the phase II? No, we expect it to be around NOK 40 million on a quarterly basis.
It's mainly impacted, of course, by enrollment, which we have included in our cash projections or cash use projection related to the treatment of those patients and some study-related activities that we have accounted for. So no, we don't expect it to deviate much from NOK 40 million on a quarterly basis. And a question about the warrant you have out in the market: how much do I have to pay per share if I exercise my warrants, and will I get the same type of share if I buy one in the market now? So the pricing of the warrants has been established, and that will be established prior to the window being opened. And it's defined upfront in the sense that it cannot be below NOK 0.10, and it cannot be above NOK 0.13. And it depends on the VWAP or the weighted average volume price before the window opens.
If you exercise the warrants at the price, which can vary between NOK 0.10-NOK 0.13, you will get shares in BerGenBio representing the shares that are outstanding and issued today as tradable shares. So it's the same share? Yes. Thank you. I think that completes the Q&A session. Thank you very much. Thanks, everyone.