NovoCure Limited (NVCR) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us to take part in NovoCure's 2020 Virtual Research and Development Day. In addition to today's prepared remarks, there will be 2 live question-and-answer session, facilitated by Dr. Piet Hinoul, NovoCure's Senior Vice President of Global Medical Affairs. [Operator Instructions] Today's presentation and a live webcast will be available on the Investor Relations page of our website. www.novocure.com, and will be available for replay for at least 14 days following the event. Before we start, I would like to remind you that our discussions during this event will include forward-looking statements, and actual results could differ materially from those projected in these statements. These statements involve a number of risks and uncertainties, some of which are beyond our control, including those risks and uncertainties described from time to time in our SEC filings. We do not intend to update publicly any forward-looking statement, except as required by law. Thank you for your interest in NovoCure. We hope that you enjoy today's event. [Presentation]

Good morning. My name is Bill Doyle. I'm NovoCure's Executive Chairman, and I am pleased to formally welcome you to NovoCure's 2020 Virtual Research and Development Day. NovoCure is a global oncology company, working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of Tumor Treating Fields. We anticipate readouts from key clinical trials over the next few years. Our plan today is to review the extensive body of Tumor Treating Fields research conducted over the past 2 decades. We will also introduce areas of ongoing research intended to identify optimal use of Tumor Treating Fields and to improve the predictive value of the scientific evidence generated. Additionally, we're excited to highlight growing interest in Tumor Treating Fields from across the global scientific community as we advance our collective mission to extend cancer survival. We believe we are in a virtuous cycle of execution and innovation at NovoCure. Our established commercial business, treating patients with GBM and MPM, continues to drive revenue growth and financial strength, which enable us to fund significant increasing investments in R&D. The clinical evidence generated informs potential opportunities to increase our addressable market through the expansion of treatable cancers and to increase efficacy through product innovation. Today, we will focus on the research and development activities intended to propel further growth in this self-reinforcing cycle. We have made incredible progress since our last R&D Day in 2016. We have grown R&D investment by more than 160%, with $112 million invested in the last 4 quarters alone. We have published promising Phase II pilot data in 3 additional solid tumor types, resulting in a Humanitarian Device Exemption FDA approval for malignant pleural mesothelioma, and the initiation of Phase III pivotal trials in lung cancer, pancreatic cancer and ovarian cancer. We've expanded our clinical pipeline to investigate Tumor Treating Fields in liver and gastric cancers. We have seen a steady increase in publications citing Tumor Treating Fields. And we believe we are at the point where Optune has clearly established its central role in the treatment of GBM. As proud as we are of the scientific progress made over the last 20 years and as clearly as we understand the ability of Tumor Treating Fields to disrupt cancer cell division, we believe we're only beginning our potential to impact oncology. Ongoing research is informing the optimal use of Tumor Treating Fields and improving the predictive value of scientific evidence generated. Our existing pipeline programs create the potential to extend the reach of Tumor Treating Fields therapy to many more cancer patients with multiple data readouts anticipated over the next few years. Interest is growing across the global scientific community to demonstrate Tumor Treating Fields' effect in multiple solid tumor targets and in combination with radiation and additional chemotherapies and immunotherapies. All of the research and development underway, both at NovoCure and across the scientific community, build upon and enrich the Tumor Treating Fields ecosystem. Translational research, clinical development and product innovation programs drive our opportunity to expand the approved indications for Tumor Treating Fields therapy. Research grants support in a vivo, in a vitro and other preclinical projects conducted by interested scientists around the globe, and investigator-sponsored trials further refine our understanding of Tumor Treating Fields' optimal use in the clinic. All of these efforts are ultimately in service of patients as the entire ecosystem strives to extend survival in some of the most aggressive forms of cancer. Our patient-forward mission is clear. This morning's agenda will focus both on translational research and on clinical development with 2 opportunities for live Q&A. We will feature 6 leaders from NovoCure's R&D teams and 5 external KOLs engaged in Tumor Treating Fields research programs. Translational research presentations will focus on how basic biology, dosimetry and product development programs can address clinical unmet needs. Clinical presentations will highlight potential combinations with chemotherapy, immunotherapy and radiation therapy. Throughout the event, you will have the opportunity to access a virtual exhibition hall featuring additional Tumor Treating Field sources. We hope you leave today as confident as we are in the potential of the Tumor Treating Fields therapy platform. With that, I will hand the program to Dr. Uri Weinberg, NovoCure's Chief Science Officer, who will discuss Tumor Treating Fields' mechanism of action.

My name is Uri Weinberg, and I'm the Chief Science Officer at NovoCure. For over a decade, I've been involved in the development of a cancer treatment called Tumor Treating Fields therapy or TTFields for short. Let me show you a brief explanation of how this treatment works. When cancer develops, we see a rapid and uncontrolled division of unhealthy cells. Electrical forces within the cell are critical for cell division, making the rapidly dividing cancer cells vulnerable to electrical interference. This is where Tumor Treating Fields come in. TTFields are electric fields due to specific frequencies that disrupt the conditions necessary for cell division. Let's look at how electric fields interact with cells. All cells are surrounded by a bilipid membrane, which separates the interior of the cell, the cytoplasm, from the space around it. This membrane prevents low frequency electric fields from entering the cell. TTFields, however, have a unique frequency range, between 100 to 500 kilohertz, enabling the electric fields to be generated through the cancer cell membrane. As healthy cells differ from cancer cells in their division rate, geometry and electric properties, the frequency of TTFields can be tuned to specifically affect the cancer cells, while leaving healthy cells mostly unaffected. Whether cells are healthy or cancerous, cell division or mitosis is the same. When mitosis starts, charged proteins within the cell, the microtubules, form the mitotic spindle. The spindle is built on electric interaction between its building blocks. During division, the mitotic spindle segregates the chromosomes, pulling them in opposite directions. As the daughter cells begin to form, electrically polarized molecules migrate towards the midline to make up the mitotic cleavage furrow. The furrow contracts and the 2 daughter cells separate. Now let's look at the same dividing cell and see how TTFields interfere with these conditions. When TTFields are generated in a dividing cancer cell, they cause the electrically charged proteins to align with the directional forces applied by the field that's preventing the mitotic spindle from forming. Electric forces also interrupt the migration of key proteins to the cell midline, disrupting the formation of the mitotic cleavage furrow. Interfering with these key processes disrupt mitosis and can lead to cell death. To deliver TTFields therapy, a portable medical device with 2 primary components is used, an electric field generator and the arrays that are placed on the skin covering the region around the tumor. When the device is turned on, TTFields are continuously generated within this specific region of the body covered by the arrays. Healthy tissues located outside of this region remain unaffected by the treatment. Ongoing research around the world expands our knowledge on TTFields and will hopefully continue to impact the lives of cancer patients and their families.

Hello, and welcome. My name is Moshe Giladi. I joined NovoCure 15 years ago. And for the past 10 years, I did our internal preclinical research activities as well as our research collaboration with many leading institutes worldwide. I feel fortunate to study TTFields ingenious invention of Professor Yoram Palti and take part in expanding the knowledge of this novel electric field-based therapy. While there are multiple other modalities in medicine which utilize electric fields, TTFields are unique in the frequencies, intensities and the mode of delivery. By tuning the frequency to several hundred kilohertz, we now have the ability to continuously generate an electric field within the cell. By doing so, we mainly affect processes which need to be carried in a very precise and orchestrated manner and that have a detrimental effect on cell fate. Probably the best example is mitosis, a process where a single cell divides into 2 identical daughter cells, as you saw in the movie. From the very early days, we noticed that TTFields disrupt key structural elements of mitosis thus leading to mitotic cell death or to the formation of compromised total cells. With that knowledge, we and others, as you will hear from Dr. Hagemann, started testing the combination of TTFields and antimitotic agents, discovering synergistic interaction in many of these cases. Three of NovoCure Phase III studies in non-small cell lung cancer, ovarian cancer and pancreatic cancer combined TTFields with antimitotic agents. TTFields' antimitotic effect is only the starting point for multiple other downstream outcomes. Those cells which did not die during mitosis are compromised. They divide slowly. Their ability to form colonies is reduced, and many of them will die shortly afterwards. Not only that, these compromised cells also demonstrate various forms of stress such as induction of autophagy and ER stress. These are the key drivers for immunogenic cell death, the kind of cell death which primes the immune system to go after the dying tumor cells. Realizing that TTFields could kickstart the cancer immunity cycle, we started combining TTFields with immune checkpoint inhibitors, NovoCure LUNAR Phase III study in non-small cell lung cancer and our recent study with Merck test the combination of TTFields and immune checkpoint inhibitors. It doesn't enter, as TTFields could prime the immune system in other ways, as you will learn later from Dr. David Tran. In recent years, multiple publication demonstrated that TTFields interfere with DNA damage repair, which, like mitosis, need to be performed in a very accurate manner and have a detrimental effect on cell fate. Indeed, the combination of treatment, which induced DNA damage, such as radiation therapy with TTFields, or better yet, with the radiation and pulp inhibitors prove to be highly synergistic in preclinical models. NovoCure recent Phase III study in GBM TRIDENT and our studies in mesothelioma, pancreatic cancer and gastric cancer combined TTField with modalities, which induced DNA damage. Fully understanding of the underlying mechanism of action, we now have a better understanding of why some cells are more susceptible to the effect of the TTFields. Based on this, we are exploring combination strategies to sensitize the less susceptible cells and enhance TTField efficacy. The story of TTFields continue to evolve all the time. In the past 2 years, we learned that TTField could affect cell membrane permeability and could also affect the blood-brain barrier integrity, of this, you will hear more from Dr. Hagemann. NovoCure's ability to make breakthroughs in some of the most aggressive types of solid tumors is the result of continuous investment in R&D and in the science of TTFields. We are developing preclinical research tools, which are offered to our many excellent collaborators worldwide. In my years in NovoCure, the number of our preclinical research scientists has multiplied by 20. This year marks our highest investment in R&D to date. We now have grant mechanism to support TTField research together with the American Association of Cancer Research, AACR. I strongly believe that in the upcoming years, TTField research will reveal many new outcomes of this therapy, and will allow us to further improve treatment efficacy. I'm now going to turn it over to my colleague, Dr. Carsten Hagemann.

Thank you, Moshe. Dear ladies and gentlemen, for the first time, I heard about TTFields in 2014 at the EANO meeting and honestly, this was very interesting because we just had published our data on synergistic effects of spindle checkpoint inhibition in combination with the spindle poison, Vincristine. The inhibitor protein kinase, Mps1, is a key regulator of the mitotic spindle checkpoint. It detects apparent spindle fiber attachment to the sister chromatids during mitosis, if they are caused by Vincristine, regulates multiple protein in complexes and thereby leads to a mitotic cell cycle arrest. This provides time for the cell to repair the damage so the cell might divide normally even with initial spindle damage. Since the effects of TTFields on spindle fibers seem to be very similar to those of Vincristine, we wondered whether a combination of spindle checkpoint inhibition and TTFields would synergistically augment the TTFields effects. We reproduced the known effect of TTFields at 200 kilohertz for our glioblastoma cell lines and treated these cells with TTFields in combination with Mps1 inhibition. While the single treatment led to a reduction in cell proliferation, the combination resulted in reduced cell numbers compared to the start of the experiment. This was due to increased cell death resulting from apparent mitosis. The upper panel shows normal mitosis, and on the right, normal nuclei of the cells. While the lower panel highlights the combination treatment leading to mitotic catastrophe, indicated by the highly apparent shape of the nucleus. We published these data in 2018. At this time, a colleague approached me with a plan to investigate drug treatment of the blood-brain barrier to better treat glioblastoma. The blood-brain barrier protects the brain from harmful substances, including drugs transported by the blood and is a special composition of the brain's blood vessels. The vessels are formed by astrocytes, pericytes and endothelial cells. The latter are connected by tight junctions, which densely seal the vessels and are the major structure of the blood-brain barrier. They prevent that many effective drugs can reach the targets inside the brain. So if any new drugs must be used in conjunction with the standard therapy, we tested the endothelial cells with TTFields. We grew these cells as monolayer, stained the tight junctions at the cell boundaries, shown in green, and treated them with different frequencies of TTFields. I did not expect to see any effect because TTFields have not been described to affect normal non malignant cells. Therefore, I was very surprised to see such major delocalization of the tight junction proteins when using TTFields at 100 kilohertz. Transendothelial electrical resistance was reduced, indicating opening of the blood-brain barrier and allowing blood-brain barrier impermeable molecules to pass through. Most striking was that these effects were reversible, so that the blood-brain barrier recovered within 72 hours after TTFields were switched off. The team of Dr. Giladi performed animal experiments for us. Mice received the contrast agent, gadolinium, which does not pass an intact blood-brain barrier and MRIs were taken before, directly after and 96 hours after end of TTFields treatment. The contrast agent only passed the blood-brain barrier and accumulated inside the brain in case of TTFields application. 96 hours after end of TTFields treatment, the blood-brain barrier recovered, confirming our in vitro data. We even have first results that the TTFields induced opening allows blood-brain barrier impermeable drugs to pass through for an effective treatment of glioblastoma. This research of the last blood-brain barrier opening through TTFields and its subsequent recovery could lead to possible clinical strategies for enhanced and more effective drug delivery for the treatment of brand tumors and other diseases of the CMS. Thank you for your attention. [Presentation]

Hello. My name is Ze'ev Bomzon, Director of Science at NovoCure. I joined NovoCure over 7 years ago. And since then, I have had the privilege to be part of the scientific and technology skill spearhead advancing the science of TTFields dosimetry and treatment planning. This spearhead has involved extensive collaborations with clinicians, physicists and engineers around the globe and at NovoCure. They establishment of prolific physics and algorithms teams dedicated to this field. It is the story of this journey that I would like to tell you today. Let me begin by defining TTFields dosimetry and treatment planning. To me, this is the scientific area concerned with: a, understanding how to define TTFields dose in a clinically meaningful manner; b, understanding how TTFields dose distribution influences patient outcome; and c, utilizing our understanding on TTFields dose to better plan treatment, for instance, plan or a placement on the skin to maximize those distribution in the tumor. The real breakthrough in this field came at the end of last year, 2019, when a collaborative study, including Dr. Matt Ballo, who will speak after me, was published in the Red Journal. This publication showed a correlation between TTFields dose of the tumor and overall survival in GBM patients. In this study, we utilized the combination of numerical simulations and mining of clinical data to: provide a clinically meaningful definition for TTFields dose; and show that within the EF-14 trial, higher TTFields dose in the tumor bed was associated with prolonged survival. The modeling methods we developed for this study as well as our understanding of not to define TTFields dose in a clinically meaningful manner have enabled us to develop MAXPOINT. MAXPOINT is a software system built to enable physicians to perform TTFields treatment planning in a patient-specific manner, utilizing computational simulations. The platform provides clinicians with tools for creating patient-specific computational models, optimizing TTFields array lens to maximize dosing target regions, as well as graphic aids for visualization of TTFields dose distributions within the patient-specific models. The platform was designed in collaboration with clinicians, including Dr. Bello and has a touch and feel similar to that of radiation [ planning ] software. It brings advanced treatment planning options into the clinic in a user-friendly manner. So how did we get you? And where are we going next? The most fundamental cornerstone for treatment planning is the ability to create computational models. This is because computational models are the only practical tool for estimating field distributions and predicting how the field will distribute the response to a series of treatment plans. First simulations of delivery of TTFields to the brain were published in 2007. Here, you can see an excerpt from the publication showing delivery of TTFields to a rat brain. Obviously, in this case, the model was highly simplified. Yet it was sufficient to establish that TTFields could be delivered at therapeutic intensities of above 1 whole centimeter to small rodents. Interestingly, the first simulations of TTFields delivery to a human brain were performed outside of NovoCure by Pedro Miranda and colleagues. These results were published just before I joined NovoCure. They were sufficient to settle the obvious skepticism about TTFields being able to be generated through the relatively insulating skull so that therapeutic intensities were obtained within the brain. This study was the first of many establishing techniques for simulating TTFields delivery in realistic human models. However, the techniques for developing realistic head models developed by Miranda and his colleagues as well as others were labor intensive and required hours to days to create a single head model. Hence, such techniques were not suitable for rapidly creating head models on a scale compatible with that required for personalized treatment planning. To overcome this problem, we developed a new model creation technique, the schematic of which you can see on this slide. This technique was utilized for the Red paper study and an improved version is used in MAXPOINT. We are now moving ahead, developing methods for creating personalized torso models, improved methods for tumor segmentation and using deep learning and continuing our study on effect of TTFields distribution on progression therapies. Combining physics with computer vision, deep learning and data mining, we hope to improve our understanding about how TTFields influences disease and are aiming to develop methods that may enable prediction of [ head ] patient outcomes in response to TTFields therapy. So what research activities make up a field of TTFields dosimetry and treatment planning? This slide shows the various topics we are interested in. These topics include: a better understanding on how to define TTFields dose and its clinical implications; understanding the biophysics of TTFields at a cellular level; improving our methods for modeling TTFields and optimizing treatment; experimental work to better characterize tissue properties and TTFields distributions; and QA, the art of understanding all uncertainties associated with the treatment plan and integrating these uncertainties in order to improve treatment plans and manage patients in an effective and realistic manner. And what is the vision for the future? To get a hang of this, it is worth looking at radiation therapy. Years ago, radiation was planned for single field using X rays. Computational capabilities and technological breakthroughs have brought about advances such as IMRT that enables accurate delivery of radiation to small tumors. I believe we are just at the beginning for TTFields therapy. At the face, just 1 step above the equivalent of single field radiation therapy. By pushing the activities I described above, you can imagine the following schematic for TTFields treatment. We will likely have advanced hardware for delivering TTFields, which we could personalize so the delivery of TTFields is optimal. Physicians would be able to perform this optimization using future versions of treatment planning software. Over time, as disease patterns change, physicians could utilize the treatment planning software to replan treatment for the patients. When the replanning is performed, all historical medical data as well as recent MRI and CT might be incorporated in the algorithms that not only suggest optimal plans based on those distributions, but also based on models and algorithms that predict how the tumor will grow in response to a given plan. I feel privileged to have played a part in this development, and I'm excited about the potential that lies ahead. And now I'd like to hand it over to my friend and colleague, Dr. Matt Ballo, to let him talk a little bit more about our treatment planning.

Thanks, Ze'ev, for that introduction. I've been asked to provide some thoughts on the research and development of Tumor Treating Fields and the management of patients with solid malignancies. I'm Matthew Ballo, a radiation oncologist at the West Cancer Center, located in Memphis, Tennessee. I first became interested in Tumor Treating Fields research in late 2015 when the preliminary results from EF-14 became available. I remember hearing the results presented at the Society of Neuro-Oncology meeting and immediately thinking that these results were going to be very important, not just for my patients with glioblastoma, but also potentially for my patients with other solid malignancies. It seemed that Tumor Treating Fields mechanism of action was sufficiently high up in cellular pathways that it was going to be very difficult for cells to develop a means of resistance. After reviewing the literature and familiarizing myself with the basic science research, I concluded that this technology would not only benefit my patients, but it would be an opportunity for our multidisciplinary group at the West Cancer Center, and it would be an opportunity for radiation oncologists to engage in the development of a new and exciting antimitotic therapy. Our neuro-oncology program was newly-established, and we were looking for ways to bring the multidisciplinary team closer together. Tumor Treating Fields clinical research and clinical implementation fit our needs perfectly. The surgeon introduces the need for multidisciplinary care, including Tumor Treating Fields at the time of diagnosis. The neuro oncologist writes the order for Optune, and the radiation oncologist, that's me, does the array layout mapping. We've even created an institutional database for our patients where we track our outcomes, patient adherence and their views towards this novel therapy. In many ways, Tumor Treating Fields served as the nighest for the advancement of our multidisciplinary activities. It was equally apparent that within the multidisciplinary team, the radiation oncologists would become the primary driver for Tumor Treating Fields acceptance. Radiation oncologists regularly visualize the spatial distribution of ionizing radiation and we're accustomed to manipulating this distribution to maximize the dose delivered to the tumor volume. That's what we do all day long. Research I performed with the physicists at NovoCure prove that just like in radiation therapy, the dose of Tumor Treating Fields is important because a higher dose translates into better tumor control. MAXPOINT, the software developed for visualizing the spatial distribution of Tumor Treating Fields, will allow radiation oncologists to manipulate the dose delivered to the tumor, and it also creates a framework for managing our patients device usage. NovoCure has gone a long way to engage radiation oncologists from around the country to help develop this software. And I'm really quite honored to be involved as one of the test sites. This software represents a potential leap forward because physician engagement leads to patient engagement. And remember, our research proves that the more patients use the device, the better their outcome. In summary, from a clinician's perspective, NovoCure has done everything right, from patient and physician engagement to device and software development, all of this with an eye towards our shared goal of improving quality of life and ultimately, improving patient survival. Thank you.

Hello, and good morning. It is a privilege to be here today to present our product development programs. My career prior to NovoCure was in venture and growth equity investments. I was fortunate to be on the team executing the first VC investment in NovoCure in 2004. And I am as excited today about the future of NovoCure as I was then. I'm confident that we can continue to build on the innovation of our founder, Professor Yoram Palti. I will start with some background on our innovation today. And then take a look forward to our next major initiatives. As a reminder, we believe that 2 key factors have the potential to increase patient survival. The first is the field intensity at the tumor location. The second is the patient's time on therapy. Accordingly, we prioritize development in terms of increasing dose and making our product easier to use. And we think about our product in terms of the device, the arrays and software applications. And we have organized our development teams to deliver innovation in each area. As you may know, we introduced product innovation as a corporate objective in 2020. And I'm happy to report that we have made tremendous progress this year. First, we advanced a new high-intensity array to a clinical trial in Q3. This new array is designed to increase the field intensity delivered to the patient's tumor. The EF-33 trial is expected to enroll 25 patients and will test the safety and effectiveness of the new array for patients with recurrent glioblastoma. Once we have the results, we will compare the safety and efficacy of the new arrays to the control data from the EF-11 study and determine the appropriate regulatory pathway. Final data from the study is expected in 2022. In addition, as you heard earlier, the MAXPOINT system has advanced into a beta test phase. We are now actively collaborating with our beta sites to refine the software to maximize the end-user experience. We believe that MAXPOINT will be an important step forward, allowing physicians to create patient-specific treatment plans to increase the delivered dose for their glioblastoma patients. We also continue to make progress on a new, more flexible torso array and on the introduction of our Gen 2 device for torso applications. Both programs have the potential to improve ease of use for our patients in our clinical trials as well as for our commercial MPM patients. I also want to spend some time talking about MyLink. As a reminder, the MyLink tool allows patients to transmit data from their device directly to our support teams. MyLink eliminates the need for our device specialists to visit the patient and connect to the device. We commenced a pilot launch of MyLink in the United States in Q2. We're happy to report that the pilot launch of MyLink was successful, and we are now rapidly expanding access to MyLink in the United States and we'll make MyLink available in Europe next month. As a reminder, we expedited the release of MyLink in response to the pandemic. MyLink helps protect our patients from potential exposure to COVID-19 by eliminating face-to-face support visits to download device data. But importantly, we also believe in the long-term potential for MyLink to help improve our patient support function. We have always known patient training and support in the first month of device use are critical. GBM is among the most aggressive cancers, and we must help the patient maximize the time on therapy right away. I will share one story that shows the potential impact of MyLink. Earlier this month, we completed a virtual patient start, providing remote training for both Optune and MyLink. This was our first virtual start with MyLink. With the MyLink tool in place, we began receiving patient compliance data within the first 24 hours following the virtual start. Normally, we would not have access to this data for at least a week. Our support teams immediately noticed gaps in treatment that indicated the patient needed additional training. Our device specialist was able to work with the caregiver to customize the support plan. And over the coming week, the patient achieved the targeted compliance rate. So overall, we believe that MyLink has the potential to improve patient safety and improve device use. While we are excited about the success this year, we know that we have much more to do in product development. As I mentioned at the beginning, our product development teams are focused on maximizing dose and increasing the ease of use. We also believe that we can increase the adoption of our products by making the devices more comfortable and easier to use. So to prepare for 2021 and beyond, we have taken a fresh look at how we prioritize product development. We started by plotting our existing programs against our design priorities to understand where we can best invest. As we went through this exercise, we found that our programs to date have often focused on a single priority of either dose or usability. Now to be clear, we believe that each existing project represents an important advance for patients. But the real imperative for our team is to focus on the projects that maximize both dose and ease of use. So today, we are happy to introduce 3 concepts for product development over the coming years. First, we are now focused on designing a next generation of arrays that are both more flexible and can deliver higher intensities. We are referring to this design as our next-gen array concept. We are currently in the design feasibility stage, testing multiple potential concepts. Second, we are looking at how software applications can support our patients and physicians. Specifically, we are thinking through how to launch in multiple additional indications that have much larger patient populations than those we serve today. We are referring to this effort as our patient-centered software application initiative. Within this program, we are focused on leveraging the unique role that NovoCure plays within oncology as we have a direct connection to the patient. We believe that we can build a series of software applications and related services that enable real-time device support interventions, both by NovoCure and the physicians. Lastly, we are going to work towards a Generation 3.0 of our Tumor Treating Fields generator. We believe, as you heard today, that we can optimize and expand the ways in which we use electric fields to treat tumors. We plan to complete design feasibility testing on several new device concepts in 2021. With all of our next-generation programs, we will provide updates once the program exits the design feasibility stage and is placed in the product development pipeline. As I close out, I want to highlight that NovoCure has aligned product development and business development under the same umbrella. We believe that Tumor Treating Fields will become a backbone therapy for solid tumor cancers, adding to surgery, radiation and systemic therapies. We recognize the need to collaborate with our industry peers to maximize patient outcomes. To that end, we were very happy in Q3 to announce our clinical collaboration with MSD, a subsidiary of Merck. Our collaboration on the Keynote-36 trial will enable us to gain critical insights on the combination of Tumor Treating Fields with an anti-PD-1 agent. We, at NovoCure, are excited about the potential to extend patient survival through product innovation, and we appreciate our investors and recognize the vital role that all of you play in helping us to serve our mission. Thank you. I'll now turn the session over to my colleague, Dr. Piet Hinoul, for a live Q&A.

Great. Frank, what a great start of the day and so much excitement around this R&D convention this morning with our investors. So lots of questions. So let us dive right in. And the first 2 questions come from Larry Biegelsen at Wells Fargo. The first one is for our Internal Chief Scientific Officer, Uri Weinberg. Uri, when it comes down to the intensity delivered, is there a limit to the amount of energy that you can deliver to the tumor? Or is there, at some point, a side effect to be expected. Uri?

Thank you, Piet. I would like to start by saying that it is great to share these presentations and messages with you despite the forced social distancing. To me, looking at this truly gives a sense of accomplishment, considering what NovoCure managed to achieve based on Professor Yoram Palti's groundbreaking invention. I would like to refer to the question and to say that to date, we have not identified dose-limiting toxicity that would limit our delivery of higher field intensities to the different regions where tumors are located in humans. Since we saw throughout our extensive clinical experience to date that the only frequent adverse event means mild to moderate skin toxicity, but there are no systemic toxicities when we delivered treatment Tumor Treating Fields to multiple cancers. We believe that we are able to deliver higher intensities of TTFields through engineering developments that Frank covered earlier and achieve greater efficacy. And that follows what Dr. Ballo demonstrated earlier and our understanding that higher intensities of TTFields would hopefully translate into greater efficacy and greater overall survival for patients.

Great, terrific. Uri. The next question, also from Mr. Biegelsen, is directed to Frank, our Chief Development Officer. Frank, Mr. Biegelsen is curious about the Gen 2 Torso device. It wasn't clear to him what exactly the benefits will be from this new version.

Well, thank you, Piet, and thank you, Larry, for the question. The -- as you may -- some of you may know from several years ago, we had moved from a Gen 1 device for our CMS applications to a Gen 2 device for the CMS applications that was roughly half the weight, half the size. And our Gen 2 Torso device will replicate that for the MPM indication, helping our patients to improve their interviews, which, as we've talked about several times, is one of our key priorities in terms of product innovation.

Great. Great. Thank you, Frank. The next question comes from Jason Bednar at Piper Sandler. Thank you for the question, and it goes to Uri. And Uri, what will be the next steps to evaluate drug delivery bypassing blood-brain barrier? Are there any specific primary or metastatic tumors that make the most sense for the initial clinical work for the blood-brain barrier application of Tumor Treating Fields?

Thank you for the question. The findings that were presented by Dr. Hagemann earlier on and were reproduced also by our research team here in Israel are very exciting and basically suggest that we can create a blood-brain barrier disruption in a temporary manner. Meaning that it is entirely reversible, allowing us to potentially deliver drugs at higher intensities and even potentially drugs that have not been able to be delivered to the brain in the past. And doing all of this, without compromising patient safety profile, meaning that the blood-brain barrier will become intact once we discontinue the delivery of TTFields at the relevant frequency, which is 100 kilohertz. We believe that following the development of this technology through our preclinical testing, we will be able to open a clinical study focusing on the blood-brain barrier relevant to our applications in oncology, focusing primarily in GBM initially, although obviously, there are implications that may go beyond this application, and we are intending to explore them as well.

Great. Great. Uri, thanks for that. And as it was such a great presentation by Dr. Hagemann, Dr. Hagemann, any perspective from your side on where to -- how -- what's the next step? And what potential applications you're thinking of First in your lab and research deal?

Yes. We have, of course, first, to check whether we really can treat the glioblastoma in the animal model. That's the next step, we are going in our cooperation with Moshe Giladi in Israel. And other applications, of course, would be other brain tumors. I'm working in the neurosurgery department so that our main focus, maybe some metastatic tumors, things like that. And what we are doing in the preclinical research now is also to translate these findings, which were done on murine cells and in the murine model, with human cells, so that we can be sure that we can reproduce our findings also in human brain barrier [indiscernible] models.

Great. Great. Thank you, Dr. Hagemann. The next question for Uri comes from Vijay Kumar at Evercore ISI. Thank you very much for the question. Uri, Mr. Kumar states that the anti-mitotic cancer drugs have shown effect on different cancer cell lines, similar to Tumor Treating Fields, but did not work on all cancers. What gives us, at NovoCure, the confidence that the Tumor Treating Field platform is a platform with a broad applicability across multiple tumors?

The answer to this question is very simple. What gives us the confidence that Tumor Treating Fields is applicably multiple different cancer indications is the data. We explored the efficacy of TTFields in multiple preclinical and clinical models throughout 20 years of extensive research and development and realized that what we perhaps anticipated ahead of time is indeed what we see in the petri dish than in humans. The fact that TTFields targets the basic building blocks of every cell division process and with the right parameter modifications and the right fine-tuning and adjustment, we are able to deliver it effectively to multiple different tumors. Right now, we have a rich pipeline, covering tumors that go beyond our late phase clinical trial program, and we intend to continue and bring those cancers to clinical trials in the near future.

Great. Great. Bill, I think you'd like to add something to that.

But I want to underline what Uri said. I think what we are attempting to communicate is, while we are at the beginning of our journey with Tumor Treating Fields, and we see tremendous opportunity to optimize the way it's delivered to patients and the combinations with other therapies that can be used. In our 20 years of research, we've never found an instance in either the preclinical research in the animal models or in our clinical program where it has not been effective. And this is, of course, across multiple tumor types in multiple conditions and in multiple models. So our -- if anything, our confidence continues to build that with the research that's ongoing, we can further improve the efficacy, but we've never seen an indication in any tumor model where the fundamental modality does not work.

Great. Thank you, Bill. Next question, I'll direct to Moshe first. Moshe, so if Tumor Treating Fields increased cell permeability when using combination with drugs, any risk that the opening of the blood-brain barrier that now these chemo agents could be harmful to normal cells?

Thank you very much for the question. So the change in cell membrane permeability, as was demonstrated by our bright colleagues from Stanford, demonstrated that the increase in permeability was only seen in cancer cells. And they checked very carefully whether this effect was also seen on normal cells, and they could not see that. And this is, of course, very assuring for us that we can continue -- apply TTFields in a safe manner as was reported in previous studies. With regard to the blood-brain barrier, we also expect that the main effect to be delivered is around the tumor. So again, based on what we have seen so far, we are very confident in the safety profile of TTFields will be maintained even in the future study.

Okay. Uri, did you want to add anything to that?

I think we are -- our philosophy has always been to work step-by-step and very thoroughly investigate any new development and any new finding that is reported to us or is found by our own research teams. And this is going to continue to be the way we work. And that gives us, so far, the credibility that what we take into the clinic, what we do is only after reassuring with the highest level of confidence, patients' safety and collecting enough preclinical efficacy data to see that there is a very good rationale for this to be translated in the clinic.

Great. Great. Great. The next question comes from Cory Kasimov at JPMorgan. It's directed to Frank. Frank, would you be able to comment on what you see as a potential future innovation around the battery used in the Tumor Treating Fields system?

Thank you, Piet. Thank you, Cory. What we interested and talked quite a bit about is that we view there are -- that there's the 2 key parameters to improve our product: one being maximizing the field intensity that we're delivering at the tumor location; and the second being the overall ease of use of the product. And the -- there's a series of innovations that I would categorize as the evolutions of the electronics and battery industry that will just naturally carry over into our products becoming smaller, lighter, easier to use. Battery technology is certainly one of those. And so we are, as we look forward to this generation 3.0, the device, looking to see how the evolving battery tech can be brought into the device to help us further reduce the way -- just make it easier to use and smaller overall. But importantly, as we move ahead and taking in some of the new kinds of treatments introduced here today, we're also looking at this next generation of our device as an opportunity to further improve how we deliver the field intensities and to increase the field intensities. We think as we move ahead, you'll be hearing, number one, a sustained cadence of innovation from us across the device array and software and services platforms. But specific to the generation 3 device, you're going to hear us speaking, both about improvements in battery technologies and general advances in making the device smaller, but also in how the device can deliver a higher field intensity.

Great. Thank you, Frank. And let me just have a quick look at the next question that has come in from Difei Yang at Mizuho, and it goes to Ze’ev Bomzon, and then I'll also turn it to Dr. Ballo. Ze’ev, for the MAXPOINT software, have you got thoughts about how it's used in the torso-based indications in mesothelioma, malignant pleural mesothelioma for example? And how much of the torso would you need to model to plan treatment? And does the change in treatment depth affect the complexity of the planning model?

Well, thank you very much for this question. It's a very technical question, and I'll try to be a little bit short on this. Based on what we already know about modeling in the torso and where we're going in results that, in fact, I even showed in the presentation out here. So let's start with the first part of the question. We know from simulations when we published various posters and work at conferences regarding delivery of TTFields for the torso. So we know that when we delivered to the torso, we're able to get very good coverage of the lungs, and we've shown that in multiple publications. In fact, theoretically, at least based on the simulations we have we're able to deliver high-field intensities to the lungs and through the entire lungs with the correct layout. The area we need to model the torso is essentially, we have to go probably from, I would say, middle of the abdomen up to about the neck in order to get reliable models and that's based on sensitivity models we've done within the lab. Looking forward at max point in the future, we are looking at developing max point for the [ first time ] in the future, and it will come out hopefully in years to come as we develop on it. And I showed you some of the first work we've done on this and are modeling creating to patient-specific torso model in the presentation.

Thank you, Zev's. So how much would you be able to lift in shifts from the GBM work to the torso application? Or would it require new code?

As I said, it will require us to make models of the patient torso, and that's something that's ongoing research, and we've made considerable developments in that area.

Understood. Okay. Dr. Paolo, was there anything you wanted to add to Zev's answer?

Yes. The only thing I really want to add is I think NovoCure is recognizing through the research that we've been doing with Zev and the other physicists is that the limitation is not a device limitation. One of the things I'm most interested in is really engaging the physicians and engaging the patients. And using the software to show the physicians that the dose can be manipulated and the dose is important. And then if it's important to the physicians, it's going to be important to the patients. So I think that -- and NovoCure is recognizing that, that the limitation is not with the device.

Absolutely. Thank you for that. And yes, the patient remains the North Star and the outcomes, this will ultimately matters. Next question comes from Greg Gilbert at Truist. And the question goes to Bill. Bill, based on the Tumor Treating Fields, being able to open the blood-brain barrier, are you thinking about studying combination of Tumor Treating Fields with drugs that may have previously failed GBM trials in themselves?

Thanks, Greg. While in these scientific presentations, we try not to get too overexcited, I think Dr. Hagemann's research is really incredibly interesting for all of us. I mean, just conceptually, if we can prove we have the ability to turn on and turn off the blood-brain barrier at will, that opens up all sorts of additional clinical strategies for oncology tumors of the brain and, of course, other CNS potential indications. Again, Dr. Hagemann mentioned that we have work to do to verify the initial findings. But absolutely, all of us who work on our clinical plans and see specific strategies for using drugs that are very effective or have proven to be very effective systemically, but have not been able to benefit patients with brain malignancies because they simply couldn't get to the tumors. So it's very, very interesting for all of us.