Q4 2019 Earnings Call
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BF-WATCH TV: BF-WATCH TV 2021
Andrew: Good morning, my name is Andrew, and I will be your conference operator today. Welcome to the Intellia Therapeutics fourth quarter and full year 2019 financial results conference call. At this time, all participants are in a listen-only mode.
Good morning. My name is Andrew and I will be your conference operator today and welcome to the intellia Therapeutics fourth-quarter and full-year 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 of the company's request. If you require operator assistance, please press star then zero at this time. I would like to turn it over to Lina Lee associate director of investor relations and until you please proceed.
Thank you Albert.
Good morning, and thank you all for joining us today to discuss until his fourth-quarter and full-year 2019 operational highlights and financial results earlier this morning. We issued a press release outlining our progress this car wash and the topics we plan to discuss on today's call. This release can be found on the investors section of our website at ww.w. This call is being broadcast live in a replay will also check archives on our website before we get started. I would like to remind you that during this call we make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information in this presentation is current as of today and until you undertakes no duty to update this information unless required by law.
Andrew: 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. If you require operator assistance, please press star then zero.
Lina Li: At this time, I would like to turn it over to Lina Li, Associate Director of Investor Relations at Intellia. Please proceed. Thank you, operator.
Lina Li: Good morning, and thank you all for joining us today to discuss Intellia's fourth quarter and full year 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.intelliatx.com. This call is being broadcast live, and a replay will also be archived on our website.
Joining me on today's call from Antalya or dr. John Letter our chief executive officer. Dr. Laura lorenzino our chief scientific officer in Glen Goddard our Chief Financial Officer following. They're prepared. Remember we will be open for Q&A for which Andrew schurmier our chief operating officer initial Kaiser. Our Deputy general counsel will also be joining for today's call John will Begin by discussing the company's highlights Laurel provide an update on our R&D progress in Glen will review our financial results from the fourth quarter and full-year 2019 with that. Let me turn the call over to our CEO John.
Lina Li: 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 sec.gov 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 law. Joining me on today's call from Intellia are Dr. John Leonard, our Chief Executive Officer, Dr. Laura Sepp Lorenzino, our Chief Scientific Officer, and Glenn Goddard, our Chief Financial Officer. Following their prepared remarks, we will be open for Q&A, to which Andrew Schirrmeyer, our Chief Operating Officer, and Nishla Kaiser, our Deputy General Counsel, will also be joining. For today's call, John will begin by discussing the company's highlights, Laura will provide an update on our R&D progress, and Glenn will review our financial results for the fourth quarter and full year of 2019. With that, let me turn the call over to our CEO, John.
Thankfully no.
Good morning, everyone and thank you for joining us today. Angelia. We're advancing our full spectrum genome-editing strategy to develop diverse pipeline of in Vivo and ex Vivo programs to address life-threatening diseases our in Vivo approach delivers, Chris Burke S9 components as the therapy and our ex Vivo approach uses Chris Burke S9 as a tool to create engineered wage based Therapies.
With strong progress across our pipeline, we believe that our modular approach and Innovative science position us well to translate genome-editing into new medicines that address critical areas above medical need we have generated robust set of preclinical data supporting our potential to cure genetic diseases with a single Administration and we're especially excited about the progress of our young people approach which we believe can capture the full promise of Novel engineered cell therapies for the treatment of cancer and autoimmune diseases on the in Vivo side with our systemic life nanoparticle based delivery system. We believe we have unlocked treatment of genetic diseases that have their origin in the liver. We've demonstrated we can selectively knockout disease-causing genes and also took the insert genes to produce normal human proteins for therapeutic purposes on the ex Vivo side. We focus on engineering lymphocytes that retain normal cell physiology. Well,
John M. Leonard: Thanks, Lina. Good morning, everyone, and thank you for joining us today.
John M. Leonard: Here at Intellia, we're advancing our full-spectrum genome editing strategy to develop a diverse pipeline of in vivo and ex vivo programs to address life-threatening diseases. Our In Vivo approach delivers CRISPR-Cas9 components as the therapy, and our Ex Vivo approach uses CRISPR-Cas9 as a tool to create engineered cell-based therapy. With strong progress across our pipeline, we believe that our modular approach and innovative science position us well to translate genome editing into new medicines that address critical areas of unmet medical need. We have generated a robust set of preclinical data supporting our potential to cure genetic diseases with a single administration. And we're especially excited about the progress of our ex vivo approach, which we believe can capture the full promise of novel engineered cell therapies for the treatment of cancer and autoimmune diseases.
getting various liquid and solid tissue cancers are approached engineering of the sites is designed to overcome the limitations of
John M. Leonard: On the in vivo side, with our systemic lipid nanoparticle-based delivery system, we believe we have unlocked the treatment of genetic diseases that have their origin in the liver. We've demonstrated we can selectively knock out disease-causing genes and also precisely insert genes to produce normal human proteins for therapeutic purposes. On the ex vivo side, we focus on engineering lymphocytes that retain normal cell physiology while targeting various liquid and solid tissue cancers. Our approach to engineering lymphocytes is designed to overcome the limitations of currently available cell-based therapy. When we look back on 2019, we made substantial progress across our pipeline and platform. We named our first development candidate, which is designed for the treatment of trans-diuretin amyloid doses, and worked expeditiously towards an IND submission for NTLA-2001. We advanced our engineered cell therapy efforts to the selection of our second development candidate, NTLA 5001, for the treatment of acute myeloid leukemia, and we demonstrate our continued leadership in progressing differentiated genome editing strategies.
currently available cell-based Therapies
When we look back on 2019, we made substantial progress across our Pipeline and platform. We nominate our first development candidate which is designed for the treatment of transthyretin amyloid choices and worked expeditiously towards an IND submission for 2001. We Advanced are engineered Cell Therapy efforts to the selection of our second development candidate until Thursday at 1 for the treatment of acute myeloid leukemia, and we demonstrate our continued leadership and progressing differentiate genome-editing strategies including Target insertion of editing both are important capabilities, which enable us to either remove and or restore function of a gene across our in Vivo NEX feeble efforts.
These accomplishments placed us in a strong position for twenty twenty which will be a significant year for our company as we advance her first crisper based therapy into the clinic with a steady stream of programs poised to follow in early January. We made several pipeline announcements first. We remain on track to submit an IND for npl a 2001 in the middle of this year. And we expected those are first patients in the second half of the Year second. We've begun ind-enabling activities for ntla 5001 and anticipate submitting an IND off the first half of next year and third we disclosed a new development program, which is designed to treat hereditary angioedema or Hae this program will utilize Nash account approach and we plan to nominate a development candidate the first half of this year.
John M. Leonard: Targeted Insertion and Consecutive Editing Both are important capabilities which enable us to either remove or restore function of a gene across our in vivo and ex vivo efforts. These accomplishments place us in a strong position for 2020, which will be a significant year for our company as we advance our first CRISPR-based therapy into the clinic with a steady stream of programs poised to follow. In early January, we made several pipeline announcements. First, we remain on track to submit an IND for NTLA-2001 in the middle of this year, and we expect to dose our first patients in the second half of this year. Second, we've begun IND enabling activities for NGLA 5001 and anticipate submitting an IND in the first half of next year.
We look forward to an exciting.
In your ahead with several important milestones in particular. This patients begin to receive are potentially Curative crisper based therapies. I'll now pass the call the law who will provide additional details on TV programs and highlight the new data presented at the Keystone Symposium earlier this month Laura. Thanks John and good morning. Everyone starting with our envelope programs are moving our lead candidate until 8:21 for translating Amelia doses or attr towards. The clinic attr is a progressive and fatal disease, but they position of misfolded TTR protein can build up in multiple organs causing diverse manifestations most commonly polyneuropathy and cardiomyopathy said, he sees can be either hereditary or not hereditary, which is also known as well type 80
John M. Leonard: And third, we disclosed a new development program designed to treat hereditary angioedema, or HAU. This program will utilize an in vivo knockout approach, and we plan to nominate a development candidate in the first half of this year. We look forward to an exciting year ahead with several important milestones, in particular as patients begin to receive our potentially curative CRISPR-based therapy. I'll now pass the call to Laura, who will provide additional details on our LEAD programs and highlight the new data presented at the Keystone Symposium earlier this month. Laura?
Laura Sepp: Thanks, John, and good morning, everyone. Starting with our in vivo programs, we're moving our lead candidate NTLA-2001 for trans-state reading amyloidosis, or ATTR, toward the clinic. ATTR is a progressive and fatal disease where the deposition of misfolded TTR protein can build up in multiple organs causing diverse disease manifestations, most commonly polyneuropathy and cardiomyopathy. The disease can be either hereditary or non-hereditary, which is also known as wild-type ATTR. With NTLA-2001, our goal is to treat patients with ATTR, both the hereditary and wildlife forms of the disease, by knocking out the TTR gene in the liver that is the source of circulating TTR proteins. We believe the potential to halt disease progression following a single course of treatment gives MTLA-2001 a differentiated profile as compared to chronic therapy. As we have seen with other rare diseases, with options becoming available for patients, there is an increase in disease awareness and diagnosis. Specific to ATTR, we believe it is a highly underdiagnosed condition, and there remains a substantial unmet medical need.
With emulate 21 our goal is to treat patients with ATT are both the hereditary and while the forms of the Disease by knocking out the gene in the live or the Visa source of circulating PDR protein. We believe the potential to hold this is progression following a single course of treatment gives until 8:21. It's dinner headed profile as compared to Chronic Therapies.
we have
In with other way of diseases with options become available for patients. There is an increase in disease awareness and diagnosis specific to a DDR. We believe it is higher under the diagnosed condition and there remains a substantial unmet medical need.
The past year we had been assembling a robust package of preclinical data to support our IND and other regulatory submissions outside of the US in December 2019, Thursday, we completed a year-long durability study of our lead L&B formulation maintaining an average reduction of over 95% of serum TTR protein after a single bulb in non-human primates for very encouraged by these results as they demonstrate that we can achieve a politically relevant levels of serum protein production. Our t t are not sure which is validated by other therapies, which demonstrate a strong correlation between Northbound of protein levels and patient outcomes, but nearing completion of phase one material manufacturing and finalizing our regulatory package for submission when appropriate we will share the finalized phase one study design we
Laura Sepp: Throughout the past year, we have been assembling a robust package of preclinical data to support our IMD and other regulatory submissions outside of the U.S. In December 2019, we completed a year-long durability study of our lead LNP formulation, maintaining an average reduction of over 95% of serum TTR protein after a single dose in non-human primates. We're very encouraged by these results as they demonstrate that we can achieve therapeutically relevant levels of serum TTR protein reduction. Our TTR knockdown approach is validated by other ATTR therapies that demonstrate a strong correlation between knockdown of serum TTR protein levels and patient outcomes. We're now nearing completion of phase one material manufacturing and finalizing our regulatory package for submission.
Take the face one trial.
Will be a single or something those studies intended to assess the safety of emulate 21, even the readily observable serum biomarker. We will be able to evaluate ethicacy by monitoring the decrease in circulating levels in patients. We remain on track to submit our application in the middle of the year and to them first patients in the second half of the Year. We're incredibly excited about moving forward with 21 and have received similarly enthusiastic feedback from Key opinion leaders about our potentially Curative single Administration treatment for add our patients as a reminder. This program is being developed as part of our collaboration with regeneron off until you as in your party.
Laura Sepp: When appropriate, we will share the finalized Phase I study design. We expect the Phase I trial will be a single ascending-dose study intended to assess the safety of mTLA-2001. Given the readily observable serum biomarker, we will be able to evaluate efficacy by monitoring the decrease in circulating TTR levels in patients. We remain on track to submit our IND application in the middle of the year and to initiate treatment for those first patients in the second half of the year.
Now moving on to our next individual program in.
January we announced over plans to utilize inaccurate approach in the liver for the treatment of hereditary angioedema. Also known as Hae for this program. We were not able to rapidly achieve nhp proof-of-concept leveraging the same LMP used for a DVR only with a different guide or name. This is a clear demonstration of the benefits of our modular approach as the eight a program Builds on the inside and infrastructure developed for the addr program.
Laura Sepp: We're incredibly excited about moving forward with NTLA-2001 and have received similarly enthusiastic feedback from key opinion leaders about our potentially curative single administration treatment for ADDR patients. As a reminder, this program is being developed as part of our collaboration with Regeneron, with Intellia as the lead partner. Now moving on to our next in vivo program, in January, we announced our plans to utilize a knockout approach in the liver for the treatment of hereditary angioedema, also known as HAE. For this program, we were able to rapidly achieve NHP proof of concept, leveraging the same LMP used for ATTR, only with a different guide RNA. This is a clear demonstration of the benefits of our modular approach as the HAE program builds on the insights and infrastructure developed for the ATTR program.
H a severe genetic disease characterized by recurrent painful and unpredictable edema in various parts of the body people with a live with a constant uncertainty off when the next well in attack will occur which can be triggered by every day events such as typing or prolong seating. It can be significantly debilitating and fatal walk-in basis most patients with h a have a C1 esterase inhibitor deficiency allowing the and regulated release and build up of a declining which is Thursday. Reality and swimming. The disease is estimated to affect one in 50,000 people.
Laura Sepp: is a rare genetic disease characterized by recurring, painful, and unpredictable edema in various parts of the body. People with H.A.E. live with a constant uncertainty of when the next swelling attack will occur, which can be triggered by everyday events such as typing or prolonged sitting. It can be significantly debilitating and fatal in certain cases.
well, the existing acute and prophylactic therapies to treat h a
It is still a disease with significant treatment burden as people with HIV require regular injections and many continue to experience unexpected attacks with this program. We aim to knock out the cable kv1. Jean to reduce the spontaneous activation of the dining credit rating system and ameliorate the frequency and intensity just bags in a j patience.
Laura Sepp: Most patients with HA have a C1 esterase inhibitor deficiency, allowing the unregulated release and buildup of radikinin, which in turn mediates vascular permeability and swelling. The disease is estimated to affect 1 in 50,000 people. While there are existing acute and prophylactic therapies to treat HAE, it is still a disease with a significant treatment burden, as people with HAE require regular injections, and many continue to experience unexpected attacks. In this program, we aim to knock out the KLKV1 gene to reduce the spontaneous activation of the kinin-radikinin system and ameliorate the frequency and intensity of attacks in HAE patients. We believe KLKV1 knockout to be safe as humans with precalicrine deficiency appear to have no known health effects. In addition, increasing calicrine and activity is a clinically validated approach towards treating HAE.
We believe one no code to be safe as humans with prekallikrein deficiency appeared to have no known health effects.
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Laura Sepp: At the recent Keystone Symposium, we showed our first preclinical data set in support of our HAE program. Following a single dose in non-human primates, we demonstrated liver knockout of KLKV1 resulting in dose-dependent reduction in serum calicrine protein levels and activity up to approximately 90%. So far, we have observed that these effects are sustained through five months in our ongoing study.
Laura Sepp: All the dose levels that we tested resulted in activity reductions expected to be therapeutically relevant in reducing attack rates. Data from these and other ongoing studies will inform our selection of a development candidate for HAE, which we expect to achieve in the first half of this year. Similar to the ATTR program, our KLKV-1 HAE program is subject to an option by Regeneron to enter into a co-development and co-commercialization agreement prior to the initiation of IND and IBM studies, with Intellia as the lead partner. We look forward to sharing additional updates on the HAE program as we believe our approach could provide a compelling treatment option for patients. Additionally, we believe that this program demonstrates how our platform's modularity supports a rapid path to nominating a development candidate.
Laura Sepp: Switching now to our ex vivo efforts in immune oncology. At Intellia, we're pursuing a T-cell receptor, or TCR-based, approach for adoptive T-cell therapy. We have chosen to pursue TCRs as they enable us to direct our engineered T-cells to a broad universe of targets. Unlike CAR-Ts, TCRs recognize epitopes derived from both surface and intracellular antigens, expanding the opportunity to address most heme and solid tumors. Furthermore, we believe that our CRISPR platform and know-how allows us to engineer TCR T-cells that closely mimic the natural biology of T-cells. In January, we announced the nomination of NTLA-5001, our wholly-owned engineered diesel therapy development candidate for the treatment of acute myeloid leukemia, or AML. MDLA-50.1 utilizes a naturally occurring TCR-directed approach to target the Wilms Tumor 1 or WT1 antigen, which is overexpressed in 90% of AML, regardless of driver mutation and disease subtype.
Laura Sepp: I'm pleased to walk through the key data presented recently at the Keystone Symposium, highlighting our path to the identification and characterization of NTLA-5001. First, in collaboration with Chiara Bonini and her team at Hospitales San Rafaele, we screened for naturally occurring TCRs that bind to a WT1 epitope efficiently processed and presented by tumor cells. These TCRs are restricted to an HLA subtype that accounts for an estimated 40-45% of the population in the US and Europe. By sourcing TCRs from healthy donors, we may minimize the risk of immune toxicity against normal tissues associated with affinity-enhanced TCRs. The lead TCR was then selected based on further characterization for specificity and potency. Second, and a key differentiator for us, is our proprietary and highly efficient CRISPR-based engineering to uniformly knock out over 98% of the endogenous TCRs alpha and beta chains and inserts the therapeutic TCR in locus with high efficiency.
Laura Sepp: Our presentation at Keystone showed that our approach resulted in improved T-cell product homogeneity with enhanced expression of an inserted therapeutic TCR and reduced the risk of unwanted reactivity against normal tissue. Using our approach, we observed transfer of the therapeutic TCR into more than 70% of T cells. Of those, greater than 95% of ADDT cells carried exclusively the therapeutic TCR. This is a significant improvement over alternative approaches that do not remove or only partially remove the endogenous TCR. For example, we observed that these alternative approaches yield T-cells with a mix of TCRs where the alpha chains of the therapeutic receptor mispair with the beta chains of the native receptors and vice versa. The result? Only a small fraction of the TCRs in each cell recognize WT1.
Laura Sepp: The mispaired TCRs not only fail to recognize the target epitope but also have the potential to lead to unwanted tuxedia. As a result of selecting a natural high-affinity TCR and applying our expertise in CRISPR engineering, the engineered T-cells healed primary AML blasts with high specificity and potency. There was also no detectable off-target reactivity against bone marrow cells that expressed low physiological levels of WT1. These results are quite exciting to us as they not only continue to demonstrate the therapeutic potential of our CRISPR-mediated approach to T-cell engineering, but they're also supportive of our development candidate NTLA-5001. We have begun IND-enabling activities and remain on track to submit an IND for NTLA-5001 in the first half of next year. However, long-term outcomes continue to be poor, with overall five-year survival below 30%. With our approach, we believe our engineered diesel therapy for AML represents an opportunity to improve these long-term outcomes, and importantly, we also believe NTLA-5001 will be broadly applicable to AML patients, regardless of the mutational background of their underlying leukemia. Additionally, as we've noted in the past, WT1 is overexpressed across many tumor types.
Laura Sepp: As such, we're actively evaluating the potential to use the same TCR construct targeting WT1 in multiple solid tumors. Additionally, outside of our wholly-owned XVO efforts, our partner Novartis has completed IND-enabling studies for CRISPR-Cas9-based therapy for the treatment of sickle cell disease. At the conclusion of our research collaboration this past December, Novartis selected certain CAR-T, hematopoietic stem cell, and ocular stem cell targets for development. Rights to all non-selected targets have reverted back to Intellia. Finally, in addition to our development programs, we have a strong research engine that continues to advance our modular platform and is focused on delivering the next wave of clinical candidates. These research programs leverage our various genome editing and delivery capabilities across a variety of diseases, including hemophilia B, alpha 1 antitrypsin deficiency, and others. We look forward to keeping you updated as we approach several important milestones in the months ahead. With that, I would like to hand over the call to Glenn to provide an overview of the fourth quarter and full year financial results.
Glenn G. Goddard: Thank you, Laura, and hello, everyone. Intellia continues to be in a strong financial position as we advance multiple programs forward into development. Our cash, cash equivalents, and markable securities as of December 31st, 2019 were $284.5 million, compared to $314.1 million as of December 31, 2018. The decrease was mainly due to cash used to fund operations of approximately $125 million, which was offset in part by $72.3 million of net equity proceeds raised from the company's at-the-market offering. Nine million of funding received under the Novartis collaboration, 9.9 million of ATTR cost reimbursements made by Regeneron, and $4.2 million in proceeds from employee-based stock. Our collaboration revenue was $10.9 million for the fourth quarter of 2019 compared to $7.9 million for the same period in 2018. The increase in collaboration revenue in 2019 was mainly driven by amounts recognized under the company's
Glenn G. Goddard: As previously disclosed, Regeneron funded approximately 50% of the development costs for the ATTR program. Starting in June, Regeneron will share approximately 25% of the worldwide development costs and future commercial profits for the ATTR program. Our R&D expenses were $31.7 million for the fourth quarter of 2019, compared to $19.9 million for the same period in 2018. This increase was mainly due to IND-enabling activities for NTLA-2001 and research efforts supporting the selection of NTLA 5001 in the expansion of our research and development. Our G&A expenses were $9 million for the fourth quarter, compared to $8.7 million for the same period last year. This increase was driven primarily by employee-related expenses. Finally, today we are reaffirming that we expect our current cash balance to fund our operating plan through at least the end of 2021. And now I'll turn the call back over to John to briefly summarize our upcoming milestones and corporate updates.
John M. Leonard: Thanks Glenn and Laura for the updates. In closing, we're extremely pleased with our recent progress. We advanced our full-spectrum strategy in 2019, guiding our lead programs towards the clinic and further establishing genome editing and delivery capabilities to enable a rapid succession of clinical candidates. Looking ahead, it is indeed an exciting time for the company as we advance our diverse pipeline for severe genetic diseases and cancer. Before we open this call for Q&A, I'd like to summarize our upcoming milestones. We remain on track to submit an IND application for NTLA-2001 in the middle of the year and plan to dose the first ATTR patients in the second half of the year. We've begun IND-enabling activities for NTLA-5001 in AML, and we plan to submit an IND application in the first half of next year.
John M. Leonard: and we expect to nominate a development candidate for our HAE program in the first half of this year.
Operator: With these anticipated milestones, alongside continued investment across our emerging pipeline, we continue to advance our mission to make genome-editing-based therapies a reality. Again, I'd like to thank you all for tuning in to the call today. We'll now open the line to any questions. Operator.
Operator: We will now begin the question and answer session. To ask a question, you may press star, then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys.
Patrick: If you want to withdraw your question, please press star than two. At this time, we will pause momentarily to assemble our roster. The first question comes from Martin Oster of Credit Suisse. Please go ahead. Hey, this is Patrick from Marty. Thanks for taking my question. Just briefly wondering if you could elaborate more on consecutive editing and then highlight any potential safety concerns around that. Thanks so much.
John M. Leonard: Thanks, Patrick. We use the term consecutive editing, meaning one LNP administration followed by another, targeting different genetic targets. An example that we've provided recently at the end of last year was with alpha-1 antitrypsin, where you could knock out the.., causative gene pathology in aberrant alpha 1 and then substitute at a different locus in that case albumin with replacement wild type gene and have that expressed and yield therapeutic proteins. It doesn't have to be that way. You could have two knockouts in two different places. You could have two different insertions. So I think we use the term generally and I think it's important to think about it that way, from a safety point of view, uh... we think about it in ways similar to a single administration so we characterize the gene that we intend to knock out uh... and we do the standard sorts of assessments for that and if we're going to insert uh... we would do a similar kind of analysis I think one point that may be implicit in your question is risk for uh... that may come from doing uh... the administrations simultaneously but in these cases uh... in all of the cases of consecutive editing that we're doing the applications are spread through time separated by days
Patrick: Got it. Thanks so much. That's very helpful. The next question comes from Maurice Raycroft of Jeffreys. Please go ahead.
Maury: Hi everyone, good morning, and congrats on the progress. The first question is on 2001 and ATTR. Just wondering what some of the feedback is that you're getting from KOLs and potentially even from patients regarding use of a one-time permanent editing method to treat disease versus chronic therapy options? And then separately, I was wondering whether the first in human studies, if you could say whether those are going to be conducted in the U.S. or the EU?
John M. Leonard: Morning. Thank you, Maury. With respect to key opinion leaders and patients, as you might imagine, we interact routinely and regularly with them because that's an important source of information to think about how these drugs will be used, the patient populations that they'll serve, and how doctors intend to administer them. And what we've seen is a very broad-based and genuine enthusiasm for the potential here. The single dose is certainly part of the appeal when you think of the alternative, which is lifelong administration of other agents. But with it, the ability to potentially have a curative approach, I think everyone has expressed broad excitement about that. So we're looking forward to seeing if we can live up to those high expectations in our clinical program and hope that we'll learn a lot more about that as we begin dosing in the second half of this year. With respect to the first in human study, could you repeat the question? I just want to make sure that...
Maury: Oh, yes.
John M. Leonard: The expectation is that we'll be in a position to have sites outside the United States in addition to the U.S. How those open and where they are is something that we'll provide in updates as we go forward, but we want to be in a position to advance the study briskly and get clinical data as quickly as possible.
Maury: Got it. Okay. And then for HAE, I'm wondering if you nominate a development candidate in the first half of 2020, based on what you've learned with ATTR, is it possible to file that HAE IND by the end of 2020?
John M. Leonard: When I nominate the DC, I will come with that information so we can all update our models and think about the way forward. I would point out that an appeal of the modular system, and this has been inherent in our thinking from the very, very beginning, is that one learns from prior experience. And it's our expectation that we'll be able to move very, very quickly once we have the appropriate target in hand and are moving forward.
Maury: Got it. Okay. And then last question, just generally about the insertion and consecutive editing techniques that you guys have been developing.
John M. Leonard: Those programs are currently wholly owned, right? And so I'm just wondering, I guess, what your plans are? Do you have plans to keep those technologies in-house or potentially outlicense them?
John M. Leonard: Yeah, thanks. Some are wholly owned; others are not. For example, we presented data on Factor IX that was done in collaboration with Regeneron, and they would certainly have rights to that, and I would stay tuned to see how that unfolds as we go forward. Alpha-1 anti-trypsin is an example of a wholly owned program. There are others that we have, but Alpha-1 is the one that we presented data most recently on, so we'll think about how we progress that as we continue to develop it.
Maury: Got it. Okay.
Maury: Thank you for taking the time. Thank you. Thank you.
David: The next question comes from Gena Wang of Barclays; please go ahead.
David: This is David in Virginia. Congratulations on the progress. I have two questions. The first one is for the ATTR program. I understand that you're not disclosing the phase one, two dose levels, but should we be expecting the starting dose to be within the therapeutic range based on your non-human primate studies? And then can you just share with us your thoughts on the modeling, the dose translation from non-human primates to humans for the study? Thanks.
John M. Leonard: David, thank you for your question. As we've shared previously, the ATTR Phase I study will be a single ascending dose study done in patients. The objective is to choose a dose that will be well on its way to being therapeutic, but drawing that line from non-human primates to humans is something that we're going to learn with this first experience. So it's very much a calculated calculation to be as close as possible, but do it in a way that permits us to live well within the therapeutic index and escalate as we go forward. So I would say in terms of modeling, what we've learned broadly from LNPs and how they're used in non-human primates is that non-human primates tend to be a pretty good predictor, and we're basing our assumptions on that.
David: Got it, very helpful. And the second question is, so again, for the Phase 1-2 program for ATTR, I'm just wondering what your thoughts are on the target TTR knockdown levels and also the target biomarker levels readout to move into a cohort expansion.
John M. Leonard: Yes, I mean, those who have gone before us and validated TTR knockdown as having therapeutic value guide us, and we're very mindful of the work that Elmylam and Ionis have done. We look at that and believe that knockdowns in excess of 60% are likely to be therapeutic, but our objective is to improve upon that. And we believe that levels that lead to lower levels of knockdown will translate to therapeutic benefit for patients. So that's what we're mindful of, and we'll see what we learn in the clinic. The specifics of cohort expansion imply a certain phase one design. We haven't revealed the phase one design, and this is something that is subject to the IND preparation that we're doing. When we're in a position to talk more exclusively about that, we'll be happy to share that information.
David: Goddard, very helpful; thank you guys.
Mani Foroohar: All right. The next question comes from Mani Foroohar of SVB Lyrinc.
John M. Leonard: Please go ahead, sir. Thank you, guys. Thanks for taking the question. A couple of quick ones. One, you, John, touched on A118 briefly and for fulfilling a couple of your comments. Can you give us an update on the status of that program and how you're thinking about that target going forward? And secondly, as the structure of your partnership with Generon has been tinkered with just a little bit, how should we think about changes in how we project OPEX tempo over the course of the next few years going forward?
Mani Foroohar: Thanks, Mani, for the question. With respect to alpha-1 antitrypsin, it's something that we're acutely interested in for, I think, all the obvious reasons. We believe the therapeutic approach that CRISPR-based gene editing brings to it is an ideal way to address the problem. The data we presented earlier as a first example of consecutive editing were done in mice, and that was something that we shared at the end of last year at ESGCT. As we've done with our other targets, the goal was to move that into models that are more relevant to humans, and so work in non-human primates and ways to optimize that are very much underway. And as we have information that's appropriate, we'll be happy to share that at upcoming scientific meetings.
John M. Leonard: Q4 OPEX is a good benchmark to use for modeling going forward into the remainder of this year and even into early 2021. I will say the financial impact of Regeneron's COCOA modification does not materially affect the runway or the OPEX. Great. Thanks for the answers, guys.
Mani Foroohar: The next question comes from Madhu Kumar of RW Baird. Please go ahead.
Madhu Kumar: Hey everyone, thank you for taking our questions. So, thinking about TTR-AMYL A dose... how long do you think you would have to monitor serum TTR levels and any declines that emerge? Do you feel comfortable that you've gotten to a potentially one-time administration leading to a permanent suppression of TTR?
John M. Leonard: Yeah, thanks for the question, Madhu. It's an important one.
John M. Leonard: We believe, based on work that we've done in animals and understanding how the protein behaves... We should be in a pretty good position with respect to knowing where we are from an editing point of view and hitting those kinds of equilibrating levels that you would get with any particular dose after about four weeks of observation. Now, whether that level is the particular level that we want at a particular dose is something that we'll learn as we carry out our Phase I study. But as you can imagine, the ability to see an effect and understand that editing is active is something that we believe we'll be able to learn very, very quickly. And that is one of the appeals of the entire TTR approach here, where you have a readily measurable serum biomarker that we do in patients. And I think we'll be in a position where we can turn that into an expectation of what that would mean for patients looking forward.
Madhu Kumar: Okay, my question is a little bit different. So yeah, certainly four weeks gets you through, based on the RNAi and antisense studies. My question is, how long after administration do you think you'd have to see durable TTR suppression? Do you feel confident that that is a one-time kind of permanent TTR suppression as compared to something that goes down and comes back up? How long is enough to feel that this could be really a one-time drug?
John M. Leonard: Yeah, I understand. We're starting with the premise that it's going to be a one-time drug, and the reason is we extrapolate from work we've done in mice and non-human primates, where we know that the LMPs deliver not only to hepatocytes, which is the source of the PTR, but also precursor cells that turn into hepatocytes. And with extended observation in those animals, what we've seen is that over the course of a lifetime in mice and over very extended observation in non-human primates, what one achieves is an invariant after that one dose. So it's clear that in humans, more time brings more confidence with that, and certainly I think the first few months of observation will be key. But again, we're starting with the expectation just based on knowing how the material is dosed and the cells that receive it that this is likely to be single-dose therapy.
Madhu Kumar: Okay, and then one last one about the Novartis Sickle Cell Program. So, as you said, they've discussed complete IND-enabling studies, and they secured some candidates. Is it reasonable to assume that the Sickle Cell Program is part of that secured candidate list? And if they were to start a clinical trial in sickle cell disease, would that be something that you would announce?
John M. Leonard: So I can't speak to the specifics of the NOVARS program. We're very excited about the work they've done. And certainly, as you know, at their R&D date, they talked about having completed IND-enabling studies. It's our expectation that if they're in a position to begin clinical work, we would certainly remind people about that, but it's not our call to action.
Madhu Kumar: Okay, great. Thanks very much.
Steven James Seedhouse: The next question comes from Steve Seedhouse of Raymond James. Please go ahead.
John M. Leonard: Hi, a couple questions on HAE. An interesting new program. This looks like a case where the gene editing approach would impact bradykinin, which is also impacted by standard of care, the C1 esterase inhibitors. Thus, the mechanism is converging on standard of care. So as you think about planning clinical development for something like that and, you know, establishing the rationale for gene editing, is it an add-on to standard of care or a replacement, or given the C1 esterase inhibitors aren't effective, I don't think, in patients with normal C1 inhibitor levels, would you target a focused subpopulation like that?
John M. Leonard: Yeah, those are important questions for the clinical program, and we haven't addressed all of them yet. Where we begin is looking at the final common pathway to bradykinin activation, which is the calocrine.
John M. Leonard: And we look at those that have gone before us with calocrine inhibitors, usually antibodies, and they set... the standard in terms of what one needs to achieve. So our expectation is that, you know, that's the benchmark. We would certainly hope to meet and improve upon that.
John M. Leonard: How those specific clinical trials are done is work that we're beginning with our KLLs, as you might imagine. When one thinks about potentially life-threatening diseases, as is the case with HAE, how one does that in the setting of existing therapy is a very careful calculation, and certainly patient safety is foremost for us. But we think we'll be able to readily determine the effect despite existing therapy, and that will be the basis for deciding how to go forward. So, early days, but we believe this is a very, very powerful way to treat essentially all patients who have underlying HAE.
John M. Leonard: Okay, and in the preclinical models you've used, or you will be using, do they recapitulate C1 inhibitor deficient disease or C1 inhibitor intact disease?
John M. Leonard: This is done in the setting of intact C1 esterase, but again, we're looking for a knockdown of the calocrine gene or pre-calocrine gene, which is that protein that ultimately activates bradykinin. So in the absence of calocrine, one does not get bradykinin activation, and that is the basis of the work that we're doing here.
John M. Leonard: And just a question on the preclinical knockdown data, the same program that is in your corporate presentation, you had three dose levels, and it looks like all three achieve 90% or higher knockdown in the case of the two highest doses. I was just curious how wide of a range those three doses cover and if you think you just overshot the minimally effective dose or is there actually a limit to the dynamic range you can achieve with in vivo dosing with this particular gene.
John M. Leonard: This is work that we typically do, which is dose ranging work to build on the database that we've built with other programs, again, working off this modular system that we have. What we showed here is a range of doses that are readily physiologically relevant to human beings, and we showed that doses that we're very familiar with, and even less than others that we've worked with in the past, are highly effective. We feel really good about moving these kinds of levels into humans and what would be a phase one study when we're ready to do that. In terms of overshooting, I would just call attention to the fact that once one edits all of the hepatocytes, you're essentially done. You've eliminated chalotrene. And this is where we can turn to nature, where we know that there are human nulls who do not have the protein at all. They have no clinically relevant conditions, and that gives us a guide, and I think it's paved the field in terms of the other inhibitors that are available, to feel quite confident about inhibiting this protein.
John M. Leonard: Okay, I appreciate that. Thank you.
Steven James Seedhouse: And then last question, quick, just regarding the selection of the sickle cell disease target by Novartis. Can you clarify what gene target that is? Is it BCL11A or something else? Thank you.
John M. Leonard: Yeah, I'd love to talk about it, but that's their story to tell.
Steven James Seedhouse: Fair enough. Thank you. The next question comes from Amanda Murphy of BTIG. Please go ahead.
Maxon: Hi everyone, this is Maxon on behalf of Amanda. Just a few high-level questions for me around strategy and oncology. First, given W21 is overexpressed in a variety of solid tumors, just seeing if you can give some additional detail around where you are in terms of narrowing down the next potential indication and what factors specifically you're evaluating as you make that decision. And then I believe last quarter you said that there would not be any edits to Intellia 501 across the indications, and just making sure that this is still the case or seeing if you're looking to make any changes to the product candidate as you expand potentially into solid tumors moving forward.
John M. Leonard: Yeah, so I'd start by saying Intel A5001 is what it is. As a product, this is an autologous lymphocyte in which the alpha and beta endogenous chains of the T cell receptor have been removed, uh... exemplified in her comments essentially completely cell that enables the insertion of the tcr that we've selected which comes again from uh... healthy donors uh... what we've tried to do here is isolate the variable which in this case is the tcr in that edited cell and the basis of the program is to take that first into liquid tumor
John M. Leonard: and then from there move into a possible range of other solitums. We've shared elsewhere, and you can see in our corporate deck, that WT1 is overexpressed across a wide range of different solid tumors, and we're exploring now, as we advance the clinical program for WT1, those other solid tumors and how they might behave. So when we have more information to share about that, believe me, we'll be happy to talk about it because we're very excited about what the potential brings. You know, the story will not stop at 50-01 for engineered cells. There's all kinds of work that we're doing, still in the research group, but that would come forward in different forms, and we'll talk more about that as those products appear.
Maxon: Okay, great, thank you. And then, just as a follow-up to that, talking about doing work in different cells, I think one of the things that we've been interested in is editing maybe NK cells and Tregs. We just wanted to see if that was something that you're evaluating as well, or if you're kind of... Focusing more on GESO specifically right now.
John M. Leonard: Yeah, it's implicit in your question is the wide range of things that one can do with gene editing, and we're certainly mindful of those things when we think about the options that we have. Currently, our focus is on the T cell receptor in lymphocytes, and the reasons for that are that we believe we've learned a lot from engineered cell therapies that have gone before us, primarily in the form of CAR T's, but we note there are many limitations to that range of approaches tends to be applicable to just a small set of tumors, and it's very well investigated by many, many different companies. We think the broader opportunity is to step out of that very crowded space and rely on the potential that TCRs bring across all kinds of other tumors. We'll think about some of those other cell types as we go forward, and we certainly have discussions about that, but right now, you should view us as primarily a TCR story.
Maxon: Okay, great. Thank you very much.
Silvan Can Tuerkcan: Sure. The next question comes from Silvan Tuerkcan of Oppenheimer. Please go ahead. Hi, good morning and congrats on the quarter. And thanks for taking my question. I just want to know about some maybe threats or gating factors that you are looking at. For example, patisserie on trial, you need to select a different kind of patients or a special kind of patients, and what have you thought about? Could these patients have taken any of the other agents before or do they have to be naive?
Silvan Can Tuerkcan: So, thanks for the questions. There are several in there.
John M. Leonard: When it comes to the specifics of the Phase I study, we'll be happy to share that after we've completed that work with the Food and Drug Administration, which all relates to this IMD filing that we're working towards. We're mindful of all of those things, and you know the nature of gene editing necessitates, One of the desirable things, treating patients. And that's why we talked earlier about working with KOLs and patient groups, et cetera. We're mindful that there are other agents out there, and we think about how to administer our drug with that as a background, which is why, again, we look to guidance from physicians.
John M. Leonard: And again, what we see is a lot of enthusiasm to do that for any number of reasons, starting with the fact that there are a set of patients that don't respond very well to the existing therapies. I think that's an easy place to begin, but we're far from limited by that patient population. And the goal of the program is to get some clinical data quickly, understand that the editing is effective, and then, as broadly and quickly thereafter, move into the full set of patients that are cardiomyopathic or neuropathic. And I think one of the exciting things about TTR that we're learning is that there are a lot more patients than anybody ever expected. And our guess is that we will recapitulate the experience that has happened in many other cases, which is when there are therapeutic modalities or diagnostic modalities, patients that weren't known about become identified, and the set of patients suitable for therapy grows substantially. I think we're already seeing that. So we're not worried about finding patients.
Silvan Can Tuerkcan: We're all worried about finding patients. Great
Silvan Can Tuerkcan: And then on the same trial, how can we use the early biomarker data that you will eventually get to triangulate kind of efficacy in either symptoms of neuropathy or cardiomyopathy to kind of think about what the profile of this drug could look like?
John M. Leonard: So, symptoms are symptoms, and that comes from interacting with patients and measuring and speaking with them, but the biomarker is a very direct measure of what is the causative pathogenic agent, which is the TTR protein itself, and I think we've learned in spades now that if one can lower TTR levels, that affects symptomatology and the physiology and clinical outcomes of patients. So it's not a surrogate marker for the Food and Drug Administration, but it's a very powerful indicator of the utility of an agent. And it lets one set up a study design to go and measure those ultimate clinical benefits. So we think it's the ideal marker and, frankly, a direct measure of the effect of the drug.
Silvan Can Tuerkcan: Great, thank you. And maybe one last question on the WT1 program. You know, you presented really great data on how you can replace the chains of a TCR. Could you already quantify the potential benefits, maybe in broad strokes, on terms of GVHD benefit or lower risk versus other CD19 CAR-T cell therapies? Or is it kind of too early to say? Are there any data sets that could hint at that?
John M. Leonard: Yeah, so it's an important question, and I guess there are two levels to that answer.
John M. Leonard: One type is the sartologous cells. So from the first perspective, one would expect no problem. The other issue here is PCRs and their specificity. You'll recall from Laura's presentation some numbers that were shared, and if you turn to our corporate website, there's a lot more information in terms of the specifics, but we believe, and I think it's just a matter of normal physiology, that if you have a TCR that is normal, coming from a normal human being, that has undergone thymic selection in the setting of a matched HLA The likelihood of a safety issue is very low.
John M. Leonard: I mean, of course, that remains to be demonstrated in the clinic, but we've done testing even in vitro where we took other cells that express low levels of WP1 and shown that the thinking is right, the specificity of the TCR is high, and the cells react only against tumor cells. Obviously, the clinical setting is the way to get the best read here, but we think the thinking and the theory are very, very sound.
John M. Leonard: Great. Yeah, thanks for taking my question. This concludes our question and answer session. I would like to turn the conference back over to Lina for any closing remarks. Thanks, and thank you all for joining today's call and for your continued interest and support. We look forward to updating you on our progress. Have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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