Earnings Call: Q2 2019

Aug 1, 2019

Good morning. My name is John, and I will be your conference operator today. Welcome to the Intellia Therapeutics Second Quarter 2019 Financial Results Conference Call. At this time, all participants are in a listen only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. At this time, I would like to turn the call over to Linda Lee, Associate Director of Intellia. Please proceed. Which was offset in part by approximately $8,000,000 of net proceeds from Thank you, operator. Good morning and thank you all for joining us today to discuss Intellia's Q2 2019 operational highlights and financial results. Earlier this morning, we issued a press release outlining our progress this quarter and the topics we plan to discuss on today's call. This release can be found on the Investors section of our website at www.inteliatx.com. This call is being broadcasted live and a replay will also be archived on our website. Before we get started, I would like to remind you that during this call, we may make certain forward looking statements and ask that you refer to our SEC filings available at bothsec.gov and our website for a discussion of potential risks and uncertainties. All information in this presentation is current as of today and Intellia undertakes no duty to update this information unless required by the law. Joining me on today's call from Intellia are Doctor. John Leonard, our President and Chief Executive Officer Doctor. Laura Sep Florenzino, our Executive Vice President and Chief Scientific Officer Glenn Goddard, our Executive Vice President and Chief Financial Officer and Jose Rivera, our Executive Vice President and General Counsel. For today's call, John will begin by discussing the company's highlights, Laura will provide an update on our R and D progress and Glenn will review our financial results from the Q2 of 20 19. Then following our prepared remarks, we will all be available for your questions. With that, let me turn the call over to John. Thanks, Lina, and thank you all for joining us today. Here at Intellia, we're pursuing a full spectrum genome editing strategy to rapidly develop a diverse pipeline of life saving therapies for patients. Our in vivo approach delivers CRISPRCas9 components as a therapy and our ex vivo approach uses CRISPRCas9 as an essential tool to create engineered cell based therapies. With our CRISPR based platform, we have the potential to cure genetic diseases with a single administration and to create novel engineered cell therapies that target various cancers and autoimmune diseases. We're proud of our innovative science and strong platform capabilities at Intellia. And we believe that the extent of our effort as well as our progress across both these areas positioned us well to deliver on our mission. Today, we built a robust set of preclinical data that demonstrates we can use systemic delivery of a CRISPRCas9 lipid nanoparticle or LNP to either selectively knock out the disease causing DNA sequence important approach in treating autosomal dominant genetic disorders or introduce a targeted insertion of DNA to make therapeutic proteins at normalizing levels, which we believe is a breakthrough approach to training autosomal recessive genetic disorders. With these in vivo capabilities, either knocking out disease causing genes or the target insertion of normal gene, we believe we have unlocked the treatment of genetic disorders that have their origin in the liver. For furthermore, we believe that these achievements serve as a foundation for targeting genetic diseases and other tissues. In addition to our in vivo effort, our ex vivo effort focuses on engineering lymphocytes that retain normal cell physiology, while targeting various hematopoietic and solid tissue cancers. Our approach to engineering lymphocytes is designed to overcome the limitations of most currently available cell based therapies. Moving to our pipeline, we've made substantial progress in advancing our lead programs towards the clinic for transthyretin amyloidosis and acute myeloid leukemia, which we will highlight on today's call. Additionally, we've expanded our R and D leadership with 2 key appointments to our management team. We're excited to welcome Doctor. Wobbe Downey, who joins us as Senior Vice President, Preclinical and Clinical Sciences. He brings with him over 2 decades of highly relevant drug development experience that is especially rich in early stage work, most recently as Vice President of Clinical Pharmacology and Pharmacometrics at AbbVie. During his tenure at AbbVie, he was instrumental in multiple drug approvals, including in biologics and small molecules such as Humira, Koolifra and Megaloxetine to name a few. She also advises the FDA on new medicines serving on 2 of their advisory committees. Walid will oversee all aspects of early development and will continue to build out her clinical development capabilities. And as we announced in May, Doctor. Laura Seth Florenzino has joined us as Executive Vice President and Chief Scientific Officer. Laura brings decades of experience in research and development, most recently as Vice President and Head of Nucleic Absence Therapies and as a member of the external innovation team at Vertex Pharmaceuticals. Earlier, during her tenure at Alnylam and Merck, Laura was a champion of nucleic acid therapies and a pioneer in advancing RNAi as a novel therapeutic modality. She will be leading our platform and drug research organization and we're already benefiting greatly from her leadership. I'm pleased to have this opportunity to introduce her today. Laura? Thank you, John, and good morning. Intellia is positioned to advance multiple programs from research to clinical development. This is a very exciting time for us as we validate our novel therapeutic modality and progress our initial programs into the clinic. I was drawn to Intellia by the breadth of the modular platform, which we're using to build the robust pipeline. The decision to pursue a chemical LMT based delivery system has established intaglia as the leader in systemic genome editing. Similarly, the application of our editing capabilities in ex vivo settings positions us to bring forth differentiated engineered cell based therapies. As I've gotten to work with the team and had the opportunity to dig into the science, I've been impressed with the talent of the team and the quality of the science. My enthusiasm has only grown and my expectations exceeded. Today, I'll be updating you on our R and D progress and pipeline, beginning on the in vivo side. As you know, our first in vivo candidate, MTLA-two thousand and one, is in development for the treatment of transderivine amyloidosis or ATTR, a disease caused by the deposition of TTR protein fibro in peripheral nerve, heart and other organs, leading to diverse disease manifestations, including peripheral neuropathy and or cardiomyopathy. The goal of NPL A201 is to reduce expression of TTR protein by knocking out the TTR gene. For reference, a delay in the clinical progression of the disease is seen with a TTR reduction of 60% or more from baseline level. As you may recall, we demonstrated an average reduction of greater than 95% of circulating DTR in non human primates at 100 days post a single administration of our lead MMT formulation targeting STENA TTR. Today, we're pleased to present additional durability data showing sustained circulating TTR protein reduction through 6 months of observation in ongoing study. We're very encouraged by these results as they show that we can achieve significant levels of TTR protein reduction expected to be clinically efficacious. As anticipated by genome editing with CRISPRCas9, once we reach these levels of protein knockdown, the effect is sustained. This data continues to underscore the power of CRISPRCas9 to develop single administration curative treatments for patients. The most recent data is consistent with earlier NHP studies in which we observed durable liver editing and concomitant TTR reduction through 10 months of observation following a single dose. We're of course eager to move this program to the clinic as soon as possible. To that end, as John mentioned, we have taken several important steps towards the clinical evaluation of NTLA-two thousand and one. Most recently, we conducted our pre IND meeting with the FDA and shortly thereafter initiated IND enabling toxicology studies, both of which will inform our IND package and the design of our Phase I study. In addition, we established supply chain operations to support manufacturing Phase 1 material expected to commence by the end of the year. Altogether, this enables us to refine our prior guidance as we now expect to submit our IND application for MDLA-two thousand and one in mid-twenty 20. As a reminder, we're the lead party for the development and commercialization of this program for which we have a fifty-fifty co development and co commercialization agreement with Regeneron. Let's now turn to our targeted insertion efforts in DELIVER. You may recall, as presented at ASGCT in April and as discussed on last quarter's call, we demonstrated the first CRISPRCas9 mediated targeted transgene insertion in the liver of nonhuman primates using Factor 9 inserted into the albumin locus. As a reminder, Factor IX encodes the blood clotting protein that's missing or defective in hemophilia B patients. The study used our proprietary hybrid delivery vehicle, which combines our CRISPR MNP delivery system with an AAV vector encoding the Factor IX gene. In a nice demonstration of the modularity of our platform, the CRISPR LNP delivery system is the same as the one used in our ATTR program with the sole change being the guide that remains. We believe our targeted insertion approach provides key advantages in both testing and efficacy. Targeted insertion should reduce the risk of mutagenesis due to random integration of retroviral vectors. In addition, targeted insertion should provide durable efficacy with a single course of treatment and potentially cure the disease. Today, we're pleased to share results from the now complete single administration NHP study showing that the circulating human Factor IX protein level observed at day 14 were durable through the 2 months of the study period. Importantly, these protein levels were within the reported range of normal circulating Factor IX protein levels in humans. The durability of serving NHP is consistent with the ROMAN study in which circulating Factor IX protein levels were sustained throughout 12 months of observation. Our targeted knockout and insertion approaches continue to validate Intellia's CRISPRCas9 platform in the in vivo setting, significantly expanding the scope of addressable genetic diseases well beyond our initial indications. We're actively working with Regeneron to progress the Factor IX program. In parallel, we're also independently evaluating several other transgene of interest as part of our wholly owned in vivo therapeutic development efforts. We look forward to updating you on our progress and we expect to present additional data on targeted insertion at upcoming scientific conference. Let's move to our engineered cell therapy strategy. Here, we're similarly leveraging a modular platform based approach to design engineered cells to treat a range of hematological and solid tumors. Our focus today will be on our T cell receptor or TCR replacement approach for our wholly owned acute myeloid leukemia or AML program. As a reminder, Intellia's TCR replacement approach docks out the endogenous TCR by eliminating alpha and beta chains and insert the therapeutic TCR in locus. We believe our TCR replacement approach should provide key expertise in both safety and efficacy. 1st, by preserving normal T cell physiology second, by enhancing and stabilizing the expression of the inserted therapeutic TCR And third, by reducing the risk of graft versus host disease that could result from mispairing between the endogenous and inserted TCRs. Further, TCRs broaden their range of addressable tumor types because they can recognize much wider repertoire tumor antigens than CAR Ts. This TCR replacement approach is the basis for our initial engineered cell therapy program for AML. AML is a cancer of the blood and bone marrow with significant unmet medical needs. The disease is rapidly fatal without immediate treatment with a less than 30% 5 year overall survival rate. In 2018, there were approximately 20,000 new cases in the U. S. Alone. Over the past 2, 3 decades, there only had been limited advances in the treatment options for AML patients. For our lead TCR based therapy for AML, we're targeting Wilms Tumor 1 or WT1. WT1 is overexpressed in greater than 90% of KML blast as well as in numerous other hematological and solid tumor types. As outlined on last quarter's call, we identified multiple lead WT1 ECR candidates that recognize the primary WT1 epitope of interest. We also have generated in vitro data showing successful and simultaneous knockout of the endogenous TCR with the insertion of various WT1 TCR candidates. The resulting engineered cells were fully functional and capable of specifically and efficiently giving a panel of patient derived AML blast. Today, we're pleased to announce that we have initiated functional testing of these lead TCRs in patient derived xenograft models, including studies with our collaborators at Hospedale San Rafaeli. These studies will inform the nomination of our 1st engineered cell therapy development candidate, which we previously guided will be by the end of this year and for which we remain on track. In addition, we're establishing contractual relationships for manufacturing capabilities to support clinical evaluation. As WT1 is overexpressed in numerous other tumor types, we believe our AML program will be the foundation to pursuing a broad array of cancers, including solid tumors. Furthermore, as we evaluate our TCR replacement approach, we expect to unlock significant immuno oncology opportunities to further expand our pipeline. With that, I would like to turn the call over to Glen, who will go through the Q2 financial statement. Glen? Thank you, Laura, and hello, everyone. Intellia remains in a strong financial position as we advance multiple programs into development. Our cash, cash equivalents and marketable securities as of June 30, 2019 were approximately 276,000,000 dollars compared to 314,000,000 as of December 31, 2018. The decrease was mainly due to cash used to fund operations of approximately $59,000,000 which was offset in part by approximately $8,000,000 of net proceeds raised from the company's at the market offering, dollars 7,000,000 of funding received under our Novartis collaboration, dollars 4,000,000 of ATTR cost reimbursements made by Regeneron and approximately $2,000,000 in proceeds from employee based stock plan. Our collaboration revenue was $11,000,000 for the Q2 of 2019 compared to $8,000,000 for the same period in 2018. As a reminder, our collaboration revenue is related to our partnership agreements with Novartis and Regeneron. Once again Regeneron is obligated to fund approximately 50% of the development costs for the ATTR program. Our R and D expenses were $26,000,000 for the Q2 of 2019 compared to $24,000,000 for the same period in 2018. As we continue to expand both our in vivo and engineered cell therapy efforts and advance our pipeline programs. Our G and A expenses were $13,000,000 for the quarter compared to $8,000,000 for the same period in 2018, largely due to an increase in legal and intellectual property costs. Finally, today, we are updating our previous guidance that we expect our cash balance as of the end of the Q2 of 2019 to fund our current operating plans into the second half of twenty twenty one. And now, I'll turn the call back over to John to briefly summarize our upcoming milestones and corporate updates. Thanks, Glenn. In closing, this is an exciting time at Intellia based on the significant progress we've made on our platform capabilities. We can knock out a disease causing DNA sequence with high levels of protein reduction. We can introduce a targeted insertion of DNA with effectively normalized protein levels and we can design engineered lymphocytes to preserve normal cell physiology. These platform capabilities along with our world class team will enable us to deliver on our mission and advance our lead programs for ATTR and AML towards the clinic. Looking ahead, we anticipate several important milestones, including the presentation of additional data from our in vivo and engineered cell therapy programs at upcoming scientific conferences by the end of 2019. Additionally, from our ATTR program, we plan to begin manufacturing the Phase 1 materials of MTLA-two thousand and one this year in support of filing an IND in mid next year. And from our AML program, we're on track to nominate a development candidate by year end. With that, I'd like to thank you all for tuning in today. We'll now open up the line to any questions. Operator? Thank We will now take our first question from Maury Raycroft of Jefferies. Please go ahead. Your line is now open. Hi, everyone. Good morning and congrats on the progress. Thanks for taking my questions. First question is just if you can provide any additional details on the pre IND meeting that you had with FDA. And also if you can provide any guidance as to when we could expect data disclosures from the IND enabling studies that you're currently working at? Good morning, Maury. It's John. Thanks for the question. First, with respect to the pre IND meeting, as you know, these meetings are about making sure you're putting in place the right assays, plans, materials, etcetera, to put together an IND. And we went through that in great detail with the FDA. They were very thoughtful, responsive, it was a very informative meeting. And what we took away was that we have the right tools and the right materials for doing the right test. So we felt very enthusiastic about the plan we've put in place. We think that again, they were very thoughtful about what we put in front of them. So, onward to the IND full speed ahead. With respect to IND enabling study data, I think we'll see that as it plays out. What I think is most relevant right now is looking ahead to some of the durability data that we've accumulated with either knock out or the insertion data on Factor IX. And as Laura said in her comments, the appropriate venues probably later this year, we'll be in a position to share some of that. So as other information becomes available, we'll look at that and if we think it's important to share it, we absolutely will. Got it. That's helpful. And then I had a question on manufacturing for the Phase I materials that you're going to be using. Just wondering if that's going to be done in house or with the CMO, and any other perspectives you could provide on manufacturing? Yes. We don't give many details, but for the purposes of the tox work and getting into clinical, it's a collection of different suppliers. We do have some material coming from outside the company and some of it we're assembling ourselves. Again, going back to the pre IND meeting, the important thing is having the right material, qualifying it correctly, doing it at the high level of quality so that you're meeting the requirements for these studies and we're checking all these boxes. Got it. Okay. And last question is just on the Novartis collaboration and with the research collaboration ending in December 2019, how should we think about that? And how should we think about potential opt in decisions from Novartis? As you point out, the collaboration is scheduled to come to a close at the end of this year. They do have certain decision rights at the end and that is yet to play out. So we're waiting to see some of the things that Novartis expects to carry forward from that program. Remember, along the way, they've expanded the relationship with Work in the Eye. So we're enthusiastic about that playing out and we're looking forward to some of the other targets that they worked on moving to the clinic at some point here. Obviously, we can't characterize that work, but we know they've been very diligently advancing some of the targets that they've been working on. So as we have more clarity, Maury, in terms of what their plans are, we'll share them, but that's information that lies ahead. We will now move on to our next question from Martin Auster of Credit Suisse. Please go ahead. Your line is open. Good morning, everyone. This is E. K. Speaking for Marty. Just had a one quick question in terms of the recently interference proceeding that was initiated between UC and Broadus Institute. I understand that it's rather early at this point, but can you walk through the expected timelines for the proceedings and the range of potential outcomes? I'll give you a short answer to the entire process. And then if you want more details, Jose or Vivek can walk us through some of the timeline things. But the bigger picture is this is part of a process that was done some time ago and this is actually the phase where inventorship will be determined. Remember earlier, the earlier proceeding addressed a different related question, which is whether or not eukaryotic cells were separately patentable, really had no bearing on exactly what we're doing. So what's happening now really is has no effect on the programs we're doing, the work that we're carrying forward, the rate at which we do it, etcetera. But maybe Jose, if you want to expand a little bit in terms of some of the time points that which we look forward to as the process unfolds. Sure. Hi, good morning. Generally, these proceedings take about 2 years from beginning to end. We would expect that this proceeding would take a similar timeframe, but divided into 2 phases. The first phase will take about a year, second phase will take about another year. In the first phase, it's all about motions and sort of trying to set the framework for the interference. In the second phase is where the Board will decide who actually invented first. That is the party that will be entitled to the patents. So ultimately, when it comes to range of options, the Board will make a decision as to who was the 1st investor of the use of the technology in the periodic sales and that party will be entitled to the patents. U. K, it's John again. I might direct you to our website where we've laid out in greater detail more about the process and in fact those particular patents that have been pulled into it. I think the important takeaway is that UC has a number of established patents that have been issued that are not affected by the process. There's a substantial number of the patents in the Broad patent mistake that had been pulled into the interference that are at stake. So we view this situation essentially as almost upside for UC where there's little to lose and much to gain and I think it's the opposite for the other side. Okay. Thank you. Sure. We will now move on to our next question from Gena Wang of Barclays. Please go ahead. Your line is open. Thank you for taking my questions. John, just wondering for the insertion, could you please remind us the Factor IX level and which methodology it was used to measure whether chromogenic assay or stage assay for non human primates? The insertion data are we're measuring milligrams per ml or actually yes, micrograms per ml, I'm sorry, I misspelled. And the normal human range falls between usually 3 to 5 micrograms per ml. I believe the asset that was used is an ELISA. And this is actually the important thing here, Tina, is not the activity of the enzyme, but we're actually measuring the amount of material that's produced in the blood. So we think that's the important takeaway here. And we also think it sets the foundation for the other insertion work that we're doing, which is if one can normalize protein levels and not just enzymatic levels, it raises opportunities for a variety of different genes in 1 with 1 insert including structural proteins. So we think that for the purposes of this experiment, the really exciting results are not activity so much, but actual amount of the material that's produced. Thank you. That's very helpful. And then for the same insertion program or the insertion approach, what would be other candidates for this LMC AAV delivery approach on your top list? Well, there's a series of transgenes that we're considering. Remember that in the liver, this is work that we collaborate with Regeneron with. So some of this is part of that collaboration and we're working very diligently We've talked a little bit about alpha-one antitrypsin in the past. We've talked a little bit about Alpha-one antitrypsin in the past. That's certainly a candidate here. We presented data on that. The full range of candidates is not something we've gone through yet, but I would say stay tuned as several of these are moving into the in life NHP phase. And we're looking for the overall generalizability of these results. And as we collect that information, we'll share it and that will certainly bear on our decisions for moving forward. Okay, great. And then lastly, training, I think following Maury's question. So could you remind us for those of you in house produced, is that research grade or clinical grade? And also any request from the FDA regarding the GMP manufacturing since you have a quite different modality, where you have ALMT, RNA and in the future will be AAV, any slots there also for the future through the CDMO or you wanted to set up some in house manufacturing capability? Sorry, basically several layers of the questions. So thank you for your question. And questions, I guess, it's true, I kept going. But they're important ones. And I think it goes all the way back to the beginning for us in terms of the actual modality that we were going to choose. And we put a lot of thought into how we were going to deliver CRISPRCas9 to the volume. As we've shared in other venues, the chemical approach, specifically lipid nanoparticles, we've felt from the beginning bring multiple different advantages, one of which is manufacturability and we'll get to that in your question here. But remember that the ease of use, you don't have to wait in line for 2 years to get to manufacturing capabilities. The cost of goods has some influence in this, trends and expression, all of those things related to the lipid nanoparticle choice that we made. Going to the FDA at the pre IND meeting, as you point out, it's very important to make sure that the various implements that are going to come together into an LNP are the right ones and that they're qualified appropriately, whether it's the nucleic acids, the lipids and then the overall way that they're tested and characterized. Was a very important part of the meeting. And it's essential to establish that those materials are properly qualified for research testing, but importantly for toxicological and ultimately clinical use. And that's what we discussed at the FDA. And we've got a sound plan in place. They saw all of the things we want to do, all the assays. And we think that we're now well positioned to take clinical grade material forward that we will manufacture, impart ourselves and in collaboration with CMOs on time into the clinic. So we feel very, very good about where we are. We will now move on to our next question from Mani Foroohra of SVB Leerink. Please go ahead. Your line is open. Hey, good morning. This is actually Rick on the line for Mani. Thank you for taking our questions. So first, I was hoping to get a little bit more visibility into the submission of the IND for 2,001. Besides the ongoing non human primate toxicology studies, are there any other major rate limiting steps that must be completed before the filing of the IND? Rick, thanks for the question. Much of this is the time that's associated with following the animals after they've been tested. And those studies have all begun. And then the manufacturing and qualifying of the material that ultimately go into patients. So I think that there are few opportunities for missteps. I mean, the work's got to be done and obviously we have to do it well, but we think that we're in a good position to do that. But we're not running a steeplechase here. This is well trod territory and we've started the process. So we feel pretty good about that IND guidance we've given based on what we know today. Thanks. That's helpful. And I have a second question that's a bit more high level. So given some of the developments in the TTR market over the past year, such as the approval of tafamidis and TTR cardiomyopathy and other competitors entering the clinic. I was just wondering, could we have your most recent thoughts on the market opportunity for TTR for gene editing and which patients do you think could be best served by 2,001? Yes. I think that it's early days for the TTR market and the modalities that have come into play are new ones for physicians. So I think it's going to be a lot of physician education that takes place. This is a market, as you know, that will be developed over time. I think this is one of those instances where it may be good to come in a little after the market's been developed and not do all the hard work that I think some of the early innovators are encountering here. But our view is that there's a large number of patients out there who will benefit from the approach. And the clinical program that we intend to put in place will address both polyneuropathy as well as cardiomyopathy. And it's our belief and I think that it's the belief of the physicians we talk to and the other innovators that are out there that as physicians think differently about heart failure in particular and start looking for those patients, there will be a substantial number of those patients that had been looked past or not identified up until now. So we'll see. And obviously, we follow this, but I wouldn't conclude anything from these early days other than there's more to learn. Just with respect to what the approach is good for with respect to patients, it's our belief that this is equally beneficial patients with neuropathy or cardiomyopathy because the ultimate therapeutic objective is to lower the protein levels. And I think that's been well established by those that have gone before us. So our clinical program is intended to study both those populations from the get go. And just to remind you, I think this is important to think about gene editing in general and the approach that we're taking. One advantage that I think will be lifelong for these patients is that this is potentially curative therapy, certainly for some conditions. And it's certainly the case that some patients may be treated with a single dose. And over the course of years of therapy, with other approaches, lifelong steroids, the economics associated with that, we think that that is an abiding advantage that will stand the test of time. All right, great. Thanks for taking our questions. We will now move on to our next question from Gula Livshitz of Chardan. Please go ahead. Your line is open. Good morning and thanks for taking my questions. So for the ATTR program, you touched a bit just now on the physician sentiment. Can you give a bit more color on any interactions you may have had with clinicians and potential study investigators in terms of what they are thinking and expectations for the potential trial? Then I have another follow-up. Sure. Thanks, Gula. We obviously talk to physicians who we want to understand what the unmet medical need is to make sure that we're designing a product that can address it. We start with that in mind. We've interacted with physicians who are very familiar with the current modalities. We've talked to patients I'm sorry, physicians who take care of patients with the conditions. We met the patients themselves in many cases. And uniformly, what we hear is that there's opportunity to improve on existing therapy, that patients have a strong interest in participating in clinical trials. And don't forget, this is one thing I've learned from talking to some of the patients that is a genetic disease in some cases, patients are very interested and motivated in finding therapies that they believe could be potentially curative for other family members. So we're not concerned that we're not going to be able to do a clinical trial or find patients. And as I said in my earlier comments, with respect to the market, I think we're in the very early days of this developing. Great. Thanks for that. And then on the WT1 program, again, congrats on the PDX studies. So are these with a targeted insertion of the TCR into the track locus or are these with viral insertion? We got about this last time also. And will we see any data on the targeted insertion before the nomination of the clinical candidate? Or kind of what are the timelines around that? Thanks. Well, I missed the first part of your I didn't hear the first part of your question. If you could just repeat it. I'm sorry, it was a little hard to hear. No, sorry about that. So the PDX studies that are now ongoing in the WT1 program, are these with targeted insertion of the TCR into the track locus or this viral insertion of the TCR in line with the data that's been presented in the past? I'm not going to be able to answer for you today that question, because I want to make sure I have the correct information so we can get a follow-up to you. The important takeaway is that the ultimate development candidate will have targeted insertion in locus. It's this notion of essentially removing what was the endogenous T cell receptor and then replacing it with a wild type T cell receptor that's been unmodified. There's no affinity enhancement. It's inserted in locus so that one can reconstitute all the physiology. AAV is certainly a way to do that and we've done that in our laboratories many times with high degrees of fidelity. There are other alternatives as well and when we get to the point of talking a little bit more about the characteristics of that development candidate, we'll go through all that data with you. Okay, great. Thanks. You bet. We will now move on to our next question from Steve Seedhouse of Raymond James. Please go ahead. Your line is open. Good morning. Thank you. I appreciate that the ongoing interference has no bearing on the R and D Intelli is doing, given you're sufficiently capitalized right now. And John, you mentioned it's basically all upside for your side in terms of the outcome of the case, but there's a pretty good increase in G and A this quarter, up 25% sequentially. So I have 3 small related questions. 1, how much is the increase sequentially directly related to legal fees? 2, what percent of your current total G and A is related to legal fees or prosecution of IP? And 3, regarding your guidance indicating cash to fund operations into 2 half twenty twenty one. How much is budgeted for legal fees in that guidance? Thanks. Glenn, do you want to address? Sure. Yes. So if you look at the quarter over quarter increase in G and A, we did indicate in the press release that a large majority of that was due to legal fees. We do have obviously the interference process going on. As you know, we also have arbitration going on with Caribou. So those are things that are driving the expenses of this quarter. In terms of the longer term view, we don't typically guide on the details of legal expenses. But we could go offline. We can discuss some of the long range plans and what goes into the runway that we've guided to. Okay. I'll follow-up offline. Thanks. Thanks, Sven. We will now move on to our next question from Madhu Kumar of R. W. Baird. Please go ahead. Your line is open. Hey guys, thanks for taking my question. So I'll keep it pretty simple. How are you thinking about a clinical trial for NTLA-two thousand and one in either hATTR polyneuropathy or cardiomyopathy? Like what are the kind of key considerations about patient population, trial design, that kind of thing? Thanks, Madhu. The earliest consideration obviously is getting into the clinic and all the focus is to do that. Then we discussed with the FDA our initial clinical plans and that was part of our pre IND meeting. So the program would begin with a fairly typical single ascending dose design and then we're discussing options to come back and either redose or multi dose to understand a little bit more about the best ways to administer the drug. It's likely that the program would bifurcate into 2 parts, 2 separate indications, cardiomyopathy and polyneuropathy. And what's driving that in the FDA's mind is that the endpoints measured are not just protein levels, but the physical measurements that come with manifestations of the disease. So the details of how exactly we'll carry out those studies lie ahead and that's work that we're doing with investigators that we talked to. Obviously, it's influenced by the regulatory input that we've gotten recently. But I think that we're in a good position to be able to carry that out. One of the things that is attractive to us about TTR is that we know what the targets are physiologically with respect to TTR circulating proteins and that will give us a very good read of where we are and where we stand competitively. We've set the bar high. We want to represent a significant therapeutic advantage for patients in addition to single dose and advantages that come with that. But we'd like to knock down TTR at least as far as the knock down and hopefully somewhat more. And we'll know that very early on. So we'll make judgments based on how we prosecute the program based on some of that early Phase I data that starts to come in. So more to follow. So then to follow-up that, what do we know from do you believe that the ONPATTRO kind of preclinical and then kind of clinical program gives you a fair way to translate preclinical LNP based drug delivery to a clinical program such that, for example, your Phase I trial, your lowest dose in a dose escalation could be therapeutic? I think that the preclinical work gives us a lot of information. Until we get into the clinic, we're not going to know exactly how valid all that information is. That's just the nature of the beast here. There's limitations until one starts to accumulate a database. But looking at what the competition has done, looking at what we've learned going cross cell types and across different species, we think we're going to have a pretty good idea of where we need to be. And then obviously in a Phase 1 study, one begins at sub therapeutic levels. And that's part of the interesting design challenges here is how far away from therapeutic this one be in within the therapeutic index that we will establish with our tox work. So there's some choices that lie ahead, but our feeling right now and the work that we've done with advisors see suggest that we'll have pretty good information to begin and of course we'll see once the Phase 1 trial begins. Okay. Thanks so much, John. Yes. Thanks for the question. And move on to our next question from Max Wach of BTIG. Please go ahead. Your line is open. Hi. Thanks for taking my questions. Just a kind of high level one for me here. Can you give us update around the status of the PH1 program? I think when we talked last quarter, you presented data around 2 separate knockout targets. So just wanted to see if any decision had been made there and what we could expect in terms of timing moving forward? Yes. Thanks for the question and thanks for watching that work. We did present work at a scientific meeting showing that 2 different targets when knocked out individually produced reductions in oxalate levels that would be expected to be therapeutic. And that work was done first as validation of the overall modular approach that we're taking. Remember that it goes back to why LMPs and how do we think about them. What we showed was that we could take essentially the same formulation, swap out a guide that's directed at a different target and with no additional manipulation, treat an animal and get a therapeutic effect. So we thought we showed that as we've shown with other targets that we've gone after. So that was an important aspect of that. PH1 itself as a therapeutic target sits in the mix of choices that we have. And it relates to a question that we were asked earlier today. Where we go next is very much a function of the work we're doing with Regeneron. Obviously, they've been partners with Factor IX and have been deeply involved with that program. There are choices that they're going through as we further analyze that data and do additional experiments. And then there's a whole set of different targets that lie between the knockouts that we've gotten reproducibly and across a variety of different targets and now gene insertion on the other end. So I think of those as the bookends of different genetic diseases in the litter. So we've not made a final decision on PH1, but there are other choices that are competing with it. And as we get the data to make that next choice, we expect to share that. Great. Thank you. And in a similar kind of manner here, just I think last quarter you talked about a fifty-fifty split between your in vivo program and your engineered cell therapy program. And going back to your point around all the considerations that go into how you think about prioritizing these programs. I guess, what do you see in terms of competition, especially within some of these hematological malignancies? And how are competitors and other companies moving into the clinic, how is that informing your actions in terms of prioritizing these programs? Yes. That is a very important question and one that we've been thinking about since the very beginning. And it relates to the collaborations we struck and the choices we've made with collaborators as well as the modalities that we pursued. I mentioned earlier on the in vivo side that we didn't want to pursue a viral delivery approach because we thought the long term sustainable advantages that come with a chemical delivery lipid nanoparticles were just too substantial to ignore. And so we took that on as our challenge and have built an in vivo program around that. Likewise, on the ex vivo side, we made the determination that CAR T lymphocytes, although a lot of activity going on in that space 4 years ago, when we were thinking about what to do, it was our belief and I think this is being borne out that it's a very crowded, somewhat poorly differentiated space with a modality that can address only a limited number of tumor types. If one needs to have large proteins that mark cells on their surfaces, the set of tumors that one can go after with CAR Ts is naturally limiting. And we see that. I mean, just look at the different antigens that people are pursuing. So we set out on what we think is a much broader platform, which is TCRs. And the decision we made was to use naturally occurring TCRs that were selected against proteins that are overexpressed in different tumor types. And that demonstrating activity in humans with that approach would open up a vast array of not only blood borne tumors, but solid tumors in any number of different epitopes that one could go after. So go back to the beginning here, in vivo, ex vivo, that's our full spectrum approach and this is about having lots of choices that we retain under our control. And secondly, designing programs so that there's nodes where we get a lot of data that determine what our next moves are. And We see those choices mounting here with excellent choices behind the doors that we're about to pass through. So as this unfolds, obviously, we'll be talking about the paths that we're going to be doubling and tripling down on. Perfect. Thank you. Thank you. We will now take our final question from Tash Hassan of ROTH Capital. Please go ahead. Your line is open. Hi, good morning. Phil in for Tony Butler here. In light of your comment about Factor IX expression in non human primates, when can we expect some detailed data, if you I mean, if you are able to speak about this, for example, which conference, that will be very helpful. Thanks for the question. I can't tell you yet which conference that will be, only because we don't have those plans in hand, right? But there is a body of work that we're going through with Regeneron with respect to Factor IX. We, 1st of all, wanted to determine the levels and that they were sustainable. And as we've shared today, we've shown that now through 2 months of observation in the in life phase, normal human levels were maintained. We think that is very important, very exciting data. Further analysis of the animals themselves as a result of that insertion are underway. Analysis of the protein, its behavior, etcetera is underway. And as we get that collected body of data and a more fulsome story, we intend to share it because we think it's state of the art and very, very exciting. Thank you for taking my question. Thanks. At this time, it appears there are no further questions. I would like to turn the conference back to Lena for any closing or additional remarks. Thanks, John. And thank you all for joining today's call and for your continued interest in Intellia. We are excited by what's still to come in 2019 and look forward to updating you on our progress. Have a great day. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.