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Visiting Moderna: Tal Zaks Talks Immunotherapy

Apr. 25, 2019

Part 1 of a two-part interview series featuring Tal Zaks, Chief Medical Officer at Moderna.

At the Cancer Immunotherapy ETF (Nasdaq: CNCR), one message we constantly reinforce is that immunotherapy is not one thing and there are many different methods to it. By taking an index approach to investing, the fund offers investors exposure to companies researching multiple methods such as cell therapy, checkpoint inhibitors, bi-specific antibodies, and others. Exposure to one new method that harnesses messenger RNA (mRNA) was gained during our semi-annual rebalance in December of 2018 when CNCR added Moderna Therapeutics to the fund. View all holdings of the CNCR ETF.

In March, the Cancer Immunothearpy ETF team had an opportunity to tour Moderna’s new state-of-the-art manufacturing facility in Norwood, Massachusetts. There we saw how mRNA therapies are produced and learned how this site has been designed to be as automated and digital as possible. It is a very impressive facility. In addition, we had the opportunity to meet with and interview members of Moderna’s senior management team to learn more about mRNA and how they are trying to harness it for use as a cancer immunotherapy.

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Today in Part 1 of our two part Moderna series, we are publishing an interview with the company’s Chief Medical Officer, Tal Zaks. Dr. Zaks describes how Moderna is using mRNA as a method for cancer immunotherapy in two ways. First, by creating therapeutic cancer vaccines that are highly personalized to the mutations in each patient’s cancer. Second, as an intratumoral product that instructs cells to produce surface proteins that will attract the immune system and teach it to recognize cancer cells. Below is a transcript of our interview, which has been minimally edited for clarity.

CNCR ETF: Thanks for hosting us today in Norwood. First, can you please introduce yourself and tell us about your background.

Dr. Zaks: My name is Tal Zaks. I am a medical oncologist by training. I am one of these guys who spent too many years in training, if you will, before going on to try to make a mark on the world. Half way through medical school I got interested in doing something a little deeper in science so I took some time off to do a Ph.D. I did it in an area of science that at the time was considered esoteric and few people were interested in it. It was cancer immunotherapy. I followed that with a postdoc, this was back in the 1990’s, at the National Cancer Institute (NCI) in the lab of Dr. Steven Rosenberg. Then after completing training, I spent my career doing drug development for oncology. The last role I had prior to joining Moderna was as the head of oncology for Sanofi, one of the large pharmaceutical companies. At that time, this was a little over four years ago, I was looking to see what kind of innovations in the ecosystem here in Boston we could leverage to make better drugs for patients and that is how I got to know Moderna. I got hooked.

What was very interesting and exciting for me was a combination of the breadth of what this platform can do in certain therapeutic areas, including cancer, and the speed at which it could conceivably move. The speed is really a testament to two things. First, is the fundamental nature of the technology—this is really synthetic biology. As you have seen here in the manufacturing systems, there is a clear line of sight. Once you design the sequence, which we call software-like, then encoding it and making a medicine or vaccine is a similar process regardless of the application, which has tremendous efficiency in terms of scalability and speed. The second factor after speed, and I give Stéphane Bancel a lot of credit for this, is the culture of the place. You have seen the digital outline. I think Stéphane from the start had a vision that we should not only make good on the promise on what this can do for one application, but we should also make sure we make good on the potential in terms of its breadth. To do that in this day and age means leveraging the best of digital technology tools that you can.

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Tal Zaks, M.D., Ph.D., Moderna’s Chief Medical Officer, discusses the Company’s pipeline of clinical programs, its work in immuno-oncology and efforts to develop personalized cancer vaccines.

“What was very interesting and exciting for me was a combination of the breadth of what this platform can do in certain therapeutic areas, including cancer, and the speed at which it could conceivably move.”
—Tal Zaks, M.D., Ph.D., Chief Medical Officer, Moderna

CNCR ETF: You mentioned that you worked for Dr. Rosenberg at the NCI. He is known as the godfather of immunotherapy and has been working on it for many decades. A lot of people were skeptical about immunotherapy back then. Having worked on it with him back before it really came to the forefront of cancer care, what has it been like to watch the progress? Were you ever skeptical yourself that this would ever reach the market one day? What has it been like to view its journey?

Dr. Zaks: It has been one of the most fascinating things I have seen in my life. To be fair, there were periods when I was skeptical as well. I think to give Dr. Rosenberg credit, what he had seen from the very first patient he ever treated is the potential for a dramatic effect. I think that is what has fueled his relentless pursuit. For those of us who have joined, it is the same because seeing it stays with you. The challenge back in the 1990’s when I was there was how do you generalize it? How do you make this applicable to more patients? I think for many years there was clearly a signal, it was clear there were patients who could respond, but it was difficult to figure out how to make it more generalizable. How could we get more patients to benefit from those early approaches because some of the patients were cured?

I then spent my career learning the drug development paradigms and working in industry. I spent some time working on what was then hot - tyrosine kinase inhibitors. Watching the field of immunotherapy come back has been phenomenal. Look, I did my postdoc on a peptide vaccine that did not work. Like many others, I was like “okay, we tried, and we don’t understand why it does not work.”

There are I think three things that have come together around the time I joined Moderna that have made it so special. First, with the advent of checkpoint inhibitors we have figured out a way to de-repress the immune system and make the phenomenal observation that Dr. Rosenberg had so many years ago in a select number of patients now applicable more broadly. Second, the science has advanced to the point that we now understand that the part of the immune system that Dr. Rosenberg has always been working on, T-cells, is the critical lynchpin. That is the part of your own body that can recognize cancer and heal it. What has become evident is that when you de-repress the immune system with a checkpoint inhibitor and ask yourself “what do these T-cells recognize?” the seminal observation is that the T-cells recognize mutations that are specific to every patient and are different among patients. I cannot overemphasize how important that is. When I was in the lab back in the 1990’s when we were trying to vaccinate patients, we were trying to use epitopes that are the body’s own epitopes. They are shared in normal tissue. They are shared between patients. However, by and large, the immune system cannot recognize them as foreign. The immune system has been trained to recognize the difference between something that is foreign from something that is self. Therefore, it is not a surprise when looking back that it is the mutations that matter. The mutations are what is different about the cancer that the rest of the body does not share. The tricky part is to figure out which mutations are these? I think one of the big challenges is that it is different in different patients. During this period we have recognized another thing that is also proving that the T-cells and how they see mutations is important. You have probably seen the results of adoptive T-cell transfer. We have learned from this that if you get the right T-cells and enough of them, one epitope is enough for recognition to cause cancer regression. That is not a trivial thing. All the cells need to see is just one epitope. If there are enough of these T-cells and you have the right biology, they cause cancer regression. How do we step back and put it all together? I think this is where Moderna’s uniqueness comes in.

It turns out, and to be fair we stumbled on this—in the early days of the company we did not envision necessarily vaccines or cancer vaccines, but what we discovered was that if we can give the information to code to make a protein in the lipid nanoparticle and we can use it as a vaccine, what we create is a very potent vaccine. When I joined Moderna about four years ago, it was clear from the infectious disease portfolio that we have a very potent vaccine platform. I think that is one of Moderna’s unique inventions—packing a messenger RNA (mRNA) in the lipid nanoparticle and using it to make a vaccine. In infectious diseases, what you look for is antibody generation. Because the mRNA gets inside the cell and creates the protein from within the cell, that is what enables it to generate not just antibodies but also to attract T-cells.

There is a very simple scientific reason. Think about what T-cells recognize. T-cells are cells in our body that are supposed to recognize another cell that has something wrong with it. How is a cell going to tell that a neighbor has been infected or invaded with something? If the invasion occurs within the other cell, how can a T-cell recognize that? Over evolution we have developed a system whereby snippets of what happens inside the cell get presented on the surface of the cell. They are sort of a barcode on the outside of the cell telling other neighbors “hey this what I have inside my house.” So T-cells constantly patrol our body looking for those barcodes and looking for ones they haven’t recognized as a sign of an intrusion. It was really over evolution that biology has evolved so that it is the primary way in which we deal with viral infections. A virus goes inside the cell, so it hides from the rest of the immune system. But because it creates these little snippets and T-cells can recognize them when they are presented. That is why, by the way, Moderna has such a potent vaccine platform for infectious disease because we mimic the virus piece. However, the other thing we are able to mimic is sending snippets to the cell surface to tell the T-cell that something is wrong. So, we know T-cells are important, and we know we have a platform that can actually create relevant snippets and present them on the cell surface so that T-cells can come in. How do we put it together now for the benefit of patients? This is the third critical piece of the puzzle.

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Roland Smith, Moderna’s senior director of GxP Digital Systems, demonstrates the company’s use of state-of-the-art digital technology at its manufacturing facility in Norwood, MA.

Because these mutations are specific to every patient, you have to go and sequence that patient’s cancer. From the vast array of mutations that happen to be there by chance and are not going to be shared by the next patient, you have to figure out which are the ones that are likely to be recognized. The cost of sequencing has gone down to the point that we can now do this routinely. In our lifetime the human genome has been read but not only that, the cost of sequencing has gone so low that now it is easy to read the genome of many people and figure out the entire genetic sequence. So what we do is take a biopsy of the tumor and also take some normal tissue and do full sequencing. Then we figure out in that full sequence, what is different from normal? So you get a list of usually a couple hundred of these epitopes that are different. Then, because we have learned in the time since I was in the lab to predict what is likely to bind to the patient’s own immune system, we put in a bioinformatics algorithm and go and figure out which of the several hundred snippets are the ones that are most likely to be recognized. We do not know for sure they will be, but there is good evidence to suggest they are likely to bind and likely to be processed. So we sequence the patient’s tumor, we figure out what is different, we then code it in an mRNA as a personalized vaccine. The next patient will have to get something different. For each patient, we go and encode the vaccine and we make it just for them. We are trying to use it to wake up the immune system. We are going to do this in combination with checkpoint inhibitors because we expect a higher benefit from that approach. We have now taken two steps forward in what the vaccine can be. First, we have realized we are probably vaccinating against the right thing, which is the specific mutations. Second, we are using a vaccine platform that is mimicking a virus in a way so it is able to attract the right kind of T-cells.

CNCR ETF: What you are describing is how hyper personalized you and others are thinking about cancer care today. We previously thought of cancer in very broad terms like “breast cancer” or “lung cancer” and what you are saying now is that you view the cancer from the specific genetic profile of the specific patient and that each patient’s cancer is different.

Dr. Zaks: Correct. I would go even a step further. There is a cool thing that I do not think many of us anticipated back in the day. We had known about oncogenes for many years - these are the mutations that drive cancer. So we started to design drugs against them. But we also knew there was a whole plethora of other mutations that at the time we thought were probably just random. We had no use for them and did not understand them. It turns out that the plethora of mutations is what the immune system uses to latch onto and recognize cancer.

It also turns out that one of the most effective ways to treat cancer is to try to get the immune system to recognize it. The reason is because the immune system is capable of traveling throughout the body and finding every cell. When we think about a cancer vaccine, there are three ways of thinking about it. First, you can try to prevent people from getting a cancer like a traditional vaccine—now that is really hard to do because these mutations are going to happen sporadically in the person’s life. I cannot vaccinate someone for cancer when they are healthy. Second, you can go to someone like what we are doing today who has cancer and sequence their tumor and try to figure out what are the mutations and then make a therapeutic vaccine. Third, you can also try to do something similar but in an earlier line of therapy. The phase 2 trial that we are about to start is in what is called the adjuvant setting. What we are doing there is going into patients that have melanoma but a relatively small tumor that was able to be surgically resected. We know these patients are in a high risk to relapse. So what we are doing is vaccinating them so that the cancer will hopefully stay away. We know that in a large proportion of them, there are micrometastatic sites already. These are cells that have escaped that we can’t find and unfortunately only time will tell when they grow back. However, the immune system can find them. If we can train the immune system to recognize them, because we have the sequence of the cancer that was just resected at surgery, then we can try to vaccinate them and improve their chances of being relapse free.

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A lab technician in Moderna’s quality control chemistry lab preparing a sample for testing. The Norwood site enables the company to manufacture, test and run fill/finish operations for its portfolio of mRNA development candidates.

CNCR ETF: Our understanding is that you are designing your vaccine using 34 epitopes. This is the part of the DNA that looks different than the healthy cells. After it is manufactured, how does the vaccine get redelivered? And how does the immune system learn from it?

Dr. Zaks: We get the biopsy and do the sequencing. That all goes into the cloud and the bioinformatics is done there. Of the 50-60 days that it takes from the time of biopsy to the time we are injecting the patient with their own personalized vaccine, this is the shortest process because it is all computing and hands off. We have an algorithm that has been validated. It takes about three hours and then the instruction set comes back down to us at the Norwood facility. We then go make it, package it, and release it. It goes back to the clinic and the patient gets injected intramuscularly just like any other vaccine. They get the injections at the same time they are getting the checkpoint inhibitor. The one we are using is Merck’s Keytruda. This happens every three weeks.

CNCR ETF: You recently increased the number of epitopes that are built into the vaccine from 20 to 34. Why did you do that and how do you even select which ones? As you mentioned, there are potentially hundreds that can be used.

Dr. Zaks: That is a good question and I am not fully satisfied by the answer. What we are doing is playing a numbers game. If a cancer has about 200 epitopes, you can rank order them based on the likelihood of them being presented. However, because we need to get it done in such a short turnaround time and from such small quantities of tissue, we do not yet have a way to validate that the epitope we are vaccinating is actually in the patient’s cancer. We think it is likely. We know the mutation is there in DNA and we double-check that the mutation is there in RNA so it is likely to be there in protein, which is what we care the most about. However, we do not know for sure. If you do not know that for sure, what we are doing is leveraging the utility of the software-like technology to say let’s load up as many of the epitopes as we think is feasible. If we give 34 instead of 20, we are creating almost twice the likelihood that the one critical epitope will be there. There may be more than one, and you can envision that if we will create T-cells against 3, 4, 5, or 10 of these mutations simultaneously, we are probably going to be more effective and less likely to see resistance crop up over time. That is why we are trying to increase the numbers.

The beauty of this platform is that everyone started with 20 because it was a reasonable number that you could get your head around and run assays in the lab on, but there is no right answer for why 20. By the way, the right answer might be different for different patients. You need to have a uniform process to put each patient through to see if your therapy works. So we started with 20 just like many others in the field, and we realized that if we take the mRNA chain and increase the length by 50%, and we have been able to do that because of advances in our technology because of what we have learned from infectious disease vaccines, and if we can make the areas that are spanning the epitopes just a tad shorter, we can squeeze in 34. We said, let’s go ahead and do that. We generated the data in the typical preclinical models to prove that if you have one, it doesn’t matter if that one is in 20 or 34, the immune system can still see it. And, by the way, it does not matter if the position of that is 1st, 10th, or 34th on the chain. The immune system can still figure it all out because that is what biology has trained it to do.

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Moderna’s preclinical mRNA operations team sets up equipment for a batch run.

CNCR ETF: Cancer vaccines are not new. People have been working on them for decades and quite frankly the success rate has not been high. There is one vaccine that is approved for prostate cancer, but other than that there have been a lot of misses in the space. Why is using mRNA potentially better than what has been tried before?

Dr. Zaks: First of all, I completely agree with you. It has been a very long and hard road for vaccines. We do not know yet that this is going to work. As I said, I started my scientific career and my postdoc doing this for a couple of years with a peptide vaccine. I don’t know that this will work. This is still experimental. However, it is worth testing because of the three new factors that we had not been able to do before.

First, we know we are immunizing against the epitopes that are more likely to give benefit. Second, we can do this in the context of a checkpoint inhibitor. You have seen the activity of checkpoint inhibitors so imagine if we are able to get more patients to respond because we are able to wake up the immune system against the right epitope in the cancer. Third, we have the mRNA technology that, because it expresses the epitopes from within a cell, it is much more likely to be recognized by the immune system and lead to an effective immune response than the traditional cancer vaccine approaches that we had used back then using peptides.

CNCR ETF: So this is entering a Phase 2 trial right now for melanoma in the adjuvant setting. The patients are receiving a combination of the vaccine and Keytruda with the hope that the combo will be better at preventing cancer returning than Keytruda alone. You are doing a randomized study, which is good because a lot of criticism of cancer research today is that there are not enough mid-stage randomized studies. So you are comparing the combo against the current standard of care. How long do you think the trial will take to enroll patients and how long are you following them to see if the cancer returns? When will you have an answer to the study?

“You are right about it being a randomized trial because for me personally, I want to know if this works. I do not want to do non-informative studies for the next ten years.”
—Tal Zaks, M.D., Ph.D., Chief Medical Officer, Moderna

Dr. Zaks: We tend not to forward guide because when you do clinical research, you are often at the behest of factors outside of your control. And this one is going to be complicated because if you think about it and you have seen it here at the manufacturing site, we are creating a bespoke vaccine for every person. We need to ensure that patient enrollment coincides with the ability to manufacture. This is quite an operational challenge making critical the close coordination between manufacturing and clinical operations eventually running the study. You are right about it being a randomized trial because for me personally, I want to know if this works. I do not want to do non-informative studies for the next ten years. We are doing an additional cohort that is a single arm in metastatic patients so we will have additional information beyond the study. But the randomized study is the one that is most likely to give us definitive results. In terms of its design, it is 150 patients. 100 will get the vaccine plus Keytruda, and 50 is a concurrent control arm that will only get Keytruda. However, we are also benefitting from the experience of Merck, who has studied Keytruda extensively in the adjuvant setting. Merck has an approval by the U.S. Food and Drug Administration for this indication. We are able to compare our 100 patients both with the 50 concurrent controls and also the data set of recent patients that have been treated. The primary endpoint is the one-year relapse free survival rate. So after we enroll everyone, we follow them for a year and then we look and compare how many unfortunately relapsed on Keytruda alone and whether we can impact that and have fewer patients relapse who get the vaccine.

CNCR ETF: What is the current standard now for patients who get Keytruda alone? What percentage typically relapses at the one-year mark?

Dr. Zaks: If you look at the most recent studies, it has been about one-third of patients. I think it then becomes a function of how much disease burden they had at the time of surgery. We stratify them by risk. Those that had smaller tumors obviously have a lower probability of relapse. What we have done with this trial, again because we want to have definitive results and to help as many patients as we can, we have actually stacked the decks against ourselves a little by preferentially enrolling patients who are at a high risk of recurrence so that we have a clear signal and that we are able to help first those patients who are in the most need.

CNCR ETF: What other potential uses are there of this? Would this be powerful enough to work outside of the adjuvant setting? Could it be a treatment against late stage cancers directly? Also, what other types of cancer besides melanoma are you thinking about using it for?

Dr. Zaks: The answer is ‘I hope so’ but we do not know yet. What the success with checkpoint inhibitors, and actually even going back to Dr. Rosenberg’s earlier results, has shown is that the immune system is powerful enough to eradicate cancer even in a patient who has metastatic and widespread disease. I think that has been a surprise to the field. Clearly checkpoint inhibitors work in the second and third lines of lung cancer. The other piece that we as a field had not necessarily expected is that cancer immunotherapy works in places like lung cancer, head & neck cancer, and bladder cancer—cancers that were not high on the list of what we had predicted. It turns out that it is mostly a function of having enough mutations in the cancer for the immune system to recognize. What we are trying to do now is go to those cancers that have a sufficient number of mutations for us to actually generate a vaccine but in which we know some will respond to checkpoint inhibitors. But the majority of patients with those tumors still do not respond. We are trying to increase the likelihood that someone who has enough mutations will respond. Our metastatic trial, which is an extension of our phase 1 experience, is open to ten different cancer types. The major determinant for us was that there is some preexisting evidence of response to a checkpoint inhibitor, even if it is not very high, and that there are enough mutations in the cancer that we can generate a vaccine.

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A poster describing Moderna’s personalized cancer vaccine unit. Moderna’s PCV is designed and manufactured individually based on the DNA sequence of a patient’s tumor and are delivered from the Norwood site directly to treatment centers for injection into patients.

CNCR ETF: To shift gears a little, this personalized cancer vaccine is only one approach Moderna has to cancer care. Another approach is called intratumoral mRNA. Your most advanced intratumoral program is using something called OX40. What is OX40 and how are you using mRNA to treat cancer with it?

Dr. Zaks: Let me start by answering your question ‘what is OX40’. It turns out, and we knew this hypothetically when I was back in the lab, is that the signal that T-cells use sometimes activates them and causes them to kill the cell while sometimes they become anergic and actually go away. It was clear hypothetically 20 years ago or so that there must be other signals that tell the T-cell how they should react when they recognize something. What is the context of recognition? OX40 ligand is part of that second group of signals (checkpoint inhibitors are another example) that will tell the T-cell ‘okay, you might have seen something that you think is foreign, but everything is fine so don’t do anything’ or ‘okay, this is inflammation and there is something wrong going on so please kill anything you see’. What we are trying to do is use mRNA to express the OX40 ligand on the surface of these cancer cells so that when a T-cell happens to come in, the T-cell will get turned on instead of turned off. We know that one reason why cancer immunotherapy does not always work more broadly is because some tumors have found ways to exclude T-cells from them or to shut down T-cells when they come in.

The beauty of using an mRNA for this is that these cells naturally work by signaling each other on the cell membrane. So how do you express a protein on a cell’s membrane? You cannot do that with standard recombinant technology. However, if you can get mRNA into the cell, it will now make a protein that will get chaperoned up to the cell surface and be displayed there. We have shown this with OX40 ligand -- that we can get it expressed on the cancer. The second thing is to think about how we can actually attract T-cells to begin with. That is the second generation of programs that we have in the clinic, which combine OX40 ligand and two other locally acting cytokines. Putting the mRNA for the cytokines in cells is like setting up local factories in the tumor just to produce that local signal to attract T-cells. They are not going everywhere in the body so this is not systemic therapy. The idea is to wake up the immune system and change the context by which it can recognize cancer.

“The beauty of using an mRNA for this is that these cells naturally work by signaling each other on the cell membrane. So how do you express a protein on a cell’s membrane? You cannot do that with standard recombinant technology.”
—Tal Zaks, M.D., Ph.D., Chief Medical Officer, Moderna

CNCR ETF: What you are describing is your triplet program. Cytokines, as you are describing, are signals that draw in and excite the immune system. So using mRNA in the way you are couldn’t be done in the past with three traditional drugs. Is that right?

Dr. Zaks: Theoretically you could make recombinant proteins and inject them locally. The problem with that is that a) you would not get expression on the membrane and b) they would immediately get diluted down in the bloodstream. So you would not get a local concentration. It would be there for seconds and then get washed out. Conversely, once an mRNA gets introduced in a cell, it will produce protein for its half-life. So if mRNA is going to last for 24-48 hours within the cells, there will be constant production of the cytokine locally where it is needed. This is mimicking biology. Think about when you get a cut on your hand and there is local healing happening. That is all cytokines working in the local microenvironment. You don’t get formation of scars all over your body if you cut your hand. It is a local effect. So if you take a cytokine like interleukin-12 (IL-12), it is a very potent thing and people thought it would work against cancer. People tried to make recombinant protein in large vats and inject it intravenously. But it is too toxic before it is effective. IL-12 is a cytokine that is not meant to work systemically. AstraZeneca has taken this idea using mRNA encoding for IL-12, which we have shown will do what it is expected to do in mouse models, and they are trying to prove it can be done in humans. They have just recently filed an application (called an IND) to start a clinical trial.

CNCR ETF: So you inject the mRNA into the cancer, but how does it work more widely? If a melanoma patient has tumors on their left arm and right arm, for example, how does it treat the whole problem if you only inject a few of the tumors on one arm?

Dr. Zaks: The concept here is that we are using the local tumor environment to wake up the immune system. Once it is woken up and once there is recognition, it is the combination with the checkpoint inhibitor that will then enable the T-cells to go wherever in the body there is cancer. I do not need my drug to go everywhere. I just need the drug to go to one place where I can wake up and stimulate specific recognition and then the immune system, especially in combination with a checkpoint inhibitor, will do the rest. This already has a proof of concept in the real world. There is a drug already on the market using this same paradigm that is approved for melanoma patients. So the concept has been validated already and that is what has generated the excitement. The first concept was done using a virus that we do not fully understand how it wakes up the immune system. We have the ability with mRNA technology to very exactly define biologically what the signal is that we want to generate. Using advances in science we have determined the cytokines that we want to be active. Now we have to go and see whether we are right.

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The entrance to Moderna’s mRNA clinical development manufacturing facility. The 200,000 sq. ft. site was opened in July of 2018 and is designed to support both pre-clinical and Phase 1 and Phase 2 clinical programs.

CNCR ETF: So right now you have a program with OX40, you have the triplet, and you have a program with AstraZeneca for IL-12. Are there other targets that you are considering right now that you can talk about?

Dr. Zaks: We have a lot of work going on in research and the team is looking at what might come next. Although we do not comment on things when they are so early. Look, I am excited about what we have in the clinic today for a couple of reasons. First, with OX40 ligand alone for us this was an important proof of pharmacology. To see if we can do this safely and if we can get protein to be made in the patient’s tumor. And does this have an effect? What we have seen is, yes, it is well tolerated. We have gone up to doses of 8 milligrams. We have also proven that we can get OX40 to be made in the patient’s cancer. This was described at a recent conference. And we saw an interesting signal from two patients with ovarian cancers whose lesions that we injected shrank. Now we didn’t get a systemic effect—it was not a response like I would hope to see. But it is a signal that we are doing something locally. We have some local activity of the protein that we are making. We have decided to push that forward and expand into a small phase 2 cohort in ovarian cancer. So I think for me is an interesting signal that we have to go figure out. Second, if you look at the total preclinical biology of what we understand about the triplet, we are really curious now that we are in dose escalation in patients to see whether alone or in combination with a checkpoint inhibitor we can impact systemic disease.

CNCR ETF: One last question. You have worked in cancer your entire career. Where do you see the future of cancer care headed? Obviously you have invested a lot in mRNA. What do you think cancer care will look like in five to ten years from now?

Dr. Zaks: I think if you connect the dots and see what the big breakthroughs have been in recent years, there are two concepts that have been glaring at us. First, there is a personalized understanding of what each individual patient needs uniquely and how each patient might be different. Second, there is the ability of the immune system to actually eradicate cancer better than any chemotherapy we have ever discovered and better than almost any tyrosine kinase inhibitor we have ever discovered. This goes back to those original observations that Dr. Rosenberg had years ago. But it happened then in a small minority of patients. Now, with the advent of science, we are starting to understand how to make it more impactful for a larger number of patients. I think connecting those dots is where I hope science will continue to advance our ability to improve clinical care and significantly prolong the lives of patients with cancer and ultimately lead to complete regressions of tumors.

CNCR ETF: Thank you for sharing your thoughts with us today. We appreciate hearing your insights.

Dr. Zaks: Thank you.

Thank you for your interest in the Cancer Immunotherapy ETF. Please check back in the future for Part 2 of our Moderna series where we interview the company’s CEO, Stéphane Bancel. Also, be sure sign up for email alerts below if you would like to receive notification of other news, company interviews, and research that we publish from time to time.

Opinions expressed are those of the author, interviewee, or Funds and are subject to change, are not intended to be a forecast of future events, a guarantee of future results, nor investment advice. Fund holdings and allocations are subject to change at any time and should not be considered a recommendation to buy or sell any security. Sanofi is not a holding of the Fund or affiliated with the Fund.


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Holdings are subject to change.

The Hong Kong Stock Exchange (HKEX) is the primary stock exchange in the Hong Kong Special Administrative Region of China. Nasdaq is one of the primary stock exchanges in the United States.

Carefully consider the Fund’s investment objectives, risk factors, charges and expenses before investing. This and additional information can be found in the Fund’s prospectus, which may be obtained at www.loncarfunds.com. Read the prospectus carefully before investing.

Investing involves risk. Principal loss is possible. The fund may trade at a premium or discount to NAV. CNCR will invest in immunotherapy companies which are highly dependent on the development, procurement and marketing of drugs and the protection and exploitation of intellectual property rights. A company’s valuation can also be greatly affected if one of its products is proven or alleged to be unsafe, ineffective or unprofitable. The costs associated with developing new drugs can be significant, and the results are unpredictable. The process for obtaining regulatory approval by the U.S. Food and Drug Administration or other governmental regulatory authorities is long and costly and there can be no assurance that the necessary approvals with be obtained and maintained. The Fund may invest in foreign securities, which involve political, economic, currency risk, greater volatility, and differences in accounting methods. The Fund is non-diversified meaning it may concentrate its assets in fewer individual holdings than a diversified fund. Therefore, the Fund is more exposed to individual stock volatility than a diversified fund. The Fund invests in smaller companies, which may have more limited liquidity and greater volatility compared to larger companies. The Fund is not actively managed and may be affected by a general decline in market segments related to the index. The fund invests in securities included in, or representative of securities included in, the index, regardless of their investment merits. The performance of the fund may diverge from that of the Index and may experience tracking error to a greater extent than a fund that seeks to replicate an index. Shares are bought and sold at market price (not NAV) and are not individually redeemed from the Fund. Brokerage commissions will reduce returns.

RISK FOR THE CHNA ETF: The biopharmaceutical industry in China is strictly regulated and changes in such regulations, including banning or limiting certain products, may have a material adverse effect on the operations, revenues, and profitability of Biopharma Companies. The laws and regulations applicable to the process of administrative approval of medicine and its production in China require entities producing biopharma products to comply strictly with certain standards and specifications promulgated by the government. Changes in currency exchange rates and the relative value of non-U.S. currencies will affect the value of the investment. Currency exchange rates can be very volatile and can change quickly and unpredictably. Investments in non-U.S. securities involve certain risks that may not be present with investments in U.S. securities. For example, investments in non-U.S. securities may be subject to risk of loss due to foreign currency fluctuations or to political or economic instability. Investments in non-U.S. securities also may be subject to withholding or other taxes and may be subject to additional trading, settlement, custodial, and operational risks. These and other factors can make investments in the Fund more volatile and potentially less liquid than other types of investments. To the extent the Fund invests a significant portion of its assets in the securities of companies of a single country or region, such as China, it is more likely to be impacted by events or conditions affecting that country or region. The Fund is a recently organized, non-diversified management investment company with no operating history. As a result, prospective investors have no track record or history on which to base their investment decision. The Fund is considered to be non-diversified, which means that it may invest more of its assets in the securities of a single issuer or a smaller number of issuers than if it were a diversified fund. The Fund is not actively managed and the Fund's sub-adviser would not sell shares of an equity security due to current or projected underperformance of a security, industry or sector, unless that security is removed from the Index or the selling of shares of that security is otherwise required upon a reconstitution of the Index in accordance with the Index methodology. To the extent the Fund invests more heavily in particular sectors of the economy, its performance will be especially sensitive to developments that significantly affect those sectors."

Diversification may not protect against market risk.

Exchange Traded Concepts, LLC serves as the investment advisor, and Vident Investment Advisory, LLC serves as a sub advisor to the fund. The Funds are distributed by Quasar Distributors, LLC, which is not affiliated with Exchange Traded Concepts, LLC or any of its affiliates.