Q1 2020 Earnings Call

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Andrew: Good morning. My name is Andrew, and I will be your conference operator today. Welcome to the Intellia Therapeutics First Quarter 2020 Financial Results Conference Call.

My name is Andrew and I will be your conference operator today welcome to the Intellia Therapeutics first quarter Twentytwenty financial results Conference call. All participants will be in listen only mode should you need assistance. Please signally conference specialist pressing the star key followed by zero.

Operator: All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's formal remarks, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your telephone keypad. To withdraw your question, please press star, then two. Please note that this event is being recorded. I would now like to turn the conference over to Lina Li, Associate Director of Investor Relations at Intellia. Please go ahead.

After todays formal remarks, there will be an opportunity to ask questions to ask your question do you mean press Star then one on your telephone keypad to withdraw your question. Please press Star then to.

Please note this event is being recorded.

I would now like to turn the conference over to lean out Lee Associate director of Investor Relations at Intellia. Please go ahead.

Thank you operator, good morning, everyone and welcome to tell you its first quarter 2020 earnings call.

Lina Li: Thank you, operator. Good morning, everyone, and welcome to Intellia's first quarter 2020 earnings call. Today we are coming to you from different locations, and we ask that you please bear with us in the event we have any audio interruptions on the call. 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 in the investors and media section of our website at www.intelliatx.com. 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 concerns.

Today, we're coming to you from different locations and we all would you. Please bear with us in the event if any audio interruptions on the call.

Earlier. This morning, we issued a press release outlining our progress this quarter the topics, we quite as discussed on today's call.

It's really is can be found on the investor and media section of our website at www, Intel yet <unk> dot com.

Called being bought Castlight and a replay will also be archived on our website.

Before we get started I like to remind you that during this call. We may make certain forward looking statements and ask you refer to our FCC filings available FCC locked up for a discussion of potential risks and uncertainties.

Lina Li: All information presented on this call is current as of today, and Intelli 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, and Andrew Schirrmeyer, our Chief Operating Officer, and Jose Rivera, our General Counsel, will also be joining. On 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 first quarter of 2020. With that, let me turn the call over to our CEO, John.

All information presented on this call is current as of today until they undertakes no duty to update this information unless required by law.

Joining me on today's call them until you are Dr., John letter, our Chief Executive Officer.

And allows us to learn do you know, our chief Scientific officer, and Glenn Goddard, Our Chief Financial Officer.

Following their prepared remarks, you will be open for two way, which Andrew sure Meier, Our Chief operating officer, and Jose Rivera, Our General Counsel will also be Johnny.

Today's call John will begin by discussing the company's highly Laurel will provide an update on the R&D progress and Glenn will review our financial results from the first quarter at 2020.

Let me turn the call older trucks, you don't.

Like Atlanta morning, everyone.

John M. Leonard: Thank you, Lena. Good morning, everyone.

John M. Leonard: We certainly appreciate your joining our call today during these challenging times. First and foremost, I hope you and your families are all staying healthy and safe. At Intellia, we continue to advance our full-spectrum strategy, applying genome editing in vivo and ex vivo to develop a diverse pipeline of novel medicines that address critical areas of unmet needs. As a reminder, our in vivo approach delivers CRISPR-Cas9 components as the therapy. With our systemic lipid nanoparticle, or LNP-based delivery system, we believe we have unlocked the treatment of genetic diseases that originate in the liver.

Certainly appreciate your joining our call today during these challenging times first and foremost I hope you and your families for all staying healthy unsafe.

And Intellia, we continue to advance for full spectrum strategy applying genome editing in vivo annex fetal to develop a diverse pipeline of novel medicines that address critical areas of unmet need.

As a reminder are in vivo approach deliberate CRISPR casnine components as a therapy.

With our systemic lip nanoparticle or LMP based delivery system. We believe we have unlock treatment of genetic diseases that are originating the liver. We've demonstrated we can selectively knockouts disease, causing jeans and also precisely interchanged to produce normal human proteins for therapeutic purposes.

John M. Leonard: We've demonstrated we can selectively knock out disease-causing genes and also precisely insert genes to produce normal human proteins for therapeutic purposes. Furthermore, a robust set of preclinical data supports our potential to cure genetic diseases with a single administration. Ex vivo, we use CRISPR-Cas9 as a tool to create engineered cell-based therapy. Here, we are redefining lymphocyte engineering to overcome many of the limitations of currently available cell-based immunotherapy. Our approach focuses on the identification of a high-affinity T-cell receptor sourced directly from a healthy donor and then engineering T-cells to only express the therapeutic TCR, which results in a homogeneous and robust cell product.

Further our robust set of preclinical data supports our potential the cure genetic diseases with a single administration.

Ex vivo, we use CRISPR casnine as a tool to create engineered cell based therapies.

Here, we are redefining lymphocyte engineering to overcome many of the limitations apparently available so based immunotherapies.

Our approach focuses on the identification of a high affinity T cell receptor sourced directly from a healthy donor and then engineering T cells to only express the therapeutic TCR, which results in a homogeneous and robust cell product. This is based on our view that engineering lymphocytes to retain normal sell physiology is key.

John M. Leonard: This is based on our view that engineering lymphocytes to retain normal cell physiology is key to the success of targeting a variety of cancers. So far in 2020, we've taken key steps in advancing our pipeline. In a matter of months, we've gone from one development candidate to three. NTLA 2001, our lead candidate, applies an in vivo liver knockout approach for the treatment of transthyretin amyloidosis or ATTR.

The success and targeting a variety of cancers.

So far and Twentytwenty, we've taken key steps and advancing our pipeline in a matter of buttons, we've gone from one development candidate three.

And T. L. A 21, our lead candidate applies and in vivo liver knockout approach for the treatment of translate written amyloidosis or a T. R.

John M. Leonard: This program continues to rapidly progress towards, and today, we are excited to announce the nomination of NTLA-2002 as a development candidate for the treatment of hereditary angioedema, or HAE. We are particularly proud of the nomination of NTLA-2002 as it also employs an in vivo liver knockout approach, demonstrating how the modularity of our platform supports a rapid progression to a clinical candidate. And with respect to our Ex Vivo pipeline, we're now in IND enabling activities for NTLA-5001, our lead TCR T-cell therapy for the treatment of acute myeloid leukemia, or AML. Before handing the call over to Laura, I'd like to take a moment to comment on the COVID-19 pandemic as it relates to our business operations and upcoming milestones. I want to start off by thanking the Intellia team for their focus and commitment to our mission and for their adaptability, which has enabled much of our work to continue under these unprecedented circumstances.

This program continues to rapidly progress towards the clinic.

Further today, we are excited to announce the nomination of into late 20th too as a development candidate for the treatment of hereditary angioedema or ha eat we are particularly proud of the nomination of Interrelate 20 out you. It's it also employers and then vivo liver knockout approach.

Constrained how the modularity of our platform supports a rapid progression to a clinical candidate.

With respect to our ex vivo pipeline, we're now and I, India, enabling activities for until a 51, our lead TCR T cell therapy for the treatment of acute myeloid leukemia or AML.

Before handing the call over to Laura I'd like to take a moment to comment on the coded 19 pandemic as it relates to our business operations and upcoming milestones.

I want to start off by thanking the intellia team for their focus and commitment to our mission for their adaptability, which have enabled much of our work to continue treating these unprecedented circumstances like.

John M. Leonard: Like many of our colleagues across the industry, we mobilize quickly to adapt to public health recommendations to ensure the safety of our team. The majority of our team continues to work remotely, with a limited number of essential personnel coming into our facilities to perform critical activities that can only be completed on site. Fortunately, at this time, we remain on track to achieve our milestones as previously guided. We recognize the risk posed by COVID-19 and are closely monitoring the situation as it continues to evolve. In particular, with respect to the planned launch of our first clinical trial, we are in active discussions with global regulatory agencies about our ATTR program. We're also in close contact with investigational sites and leading physicians around the globe to ensure patient safety and the smooth initiation of a planned clinical trial this year. I'd like to now pass the call over to Laura, who will provide additional details on our lead programs.

Like many of our colleagues across the industry, we mobilized quickly to adapt a public health recommendations to ensure the safety of her team.

The majority of our team continues to work remotely with a limited number of a central personnel coming into our facilities to perform critical activities I can only be completed onsite.

Fortunately at this time, we remain on track to a cheaper milestones as previously guided we recognize the risk posed by cobot 19 and are closely monitoring the situation. That's it continues to evolve.

In particular with respect to the planned launch where first clinical trial. We're in active discussions with global regulatory agencies about EUR eight TTR program. We're also in close contact with investigational sites and leading physicians around the globe to ensure a patient safety and smooth initiation of planned clinical trial this year.

I'd like to now pass the call of Florida, who will provide additional details on R&D programs.

Thank you John and good morning, everyone I will start with I would need Invivo program, India May 20, a one in development for the treatment of 80, PR progressive and people. They see closely the deposition deal that we told the TTR protein multiple argues it can be either.

Laura Sepp: Thank you, John, and good morning, everyone. I will start with our lead in vivo program, MDLA-2001, in development for the treatment of ATTR, a progressive and fatal disease caused by the deposition and buildup of misfolded TTR protein in multiple organs. It can be either hereditary or non-hereditary, known as wild-type ATTR, and can result in diverse disease manifestations, most commonly polyneuropathy and cardiomyopathy. MDLA-2001 uses our in vivo approach to knock out the TTR gene in the liver, which is the source of circulating TTR protein. Approved treatments for ATTR have both clinically validated the rationale for knocking down TTR and also increased disease awareness. Nevertheless, we believe it is a highly underdiagnosed condition for which unmet needs remain.

Our hereditary or non surety diary known as wild type MPPR and can be sold diversities Mason station, most commonly polyneuropathy <unk>.

And then they 21 applies I would it be will approach to walk out of the PDR, Jean Yves in liver, which used to source circulating T I probably.

Above treatments for ATP are both anybody they did a rationale for knocking down TTR <unk> Oh seem crazy awareness.

Well, we made it easy Jaime I don't think most condition per week and it needs to.

Moreover, I. So we're beginning to lead to have shown we believe in DNA 20 alone has the potential to coal disease progression with a single closest treatment well trained and differentiated profile as compared to chronic therapy timetable.

Laura Sepp: Moreover, as our preclinical data have shown, we believe NTLA-2001 has the potential to halt disease progression with a single course of treatment, offering a differentiated profile as compared to chronic therapies currently available. We're pursuing a global development strategy for NTLA-2001 to support regulatory submissions in multiple geographic regions where the patient population and qualified investigators reside. In addition, it has provided us with flexibility to address the challenges created by the pandemic. As John noted earlier, we have been speaking with regulatory bodies around the world and are committed to pursuing the most efficient path to begin the clinical program this year. This quarter, we manufacture Phase I materials, are finalizing regulatory documents, and remain on track to submit our IND, or IND equivalent, mid-year. As previously shared, the Phase 1 trial will be a single ascending-dose study in DTR patients intended to assess the safety of NTLA-2001. Given the readily observable serum biomarker, we will also be able to

We're pursuing the global development strategy for LTL. They play a one to support regulatory submissions in multiple geographic regions, where the patient population unqualified investigate that's true side.

<unk> has provided us flexibility to address it challenges created by the <unk>.

As John noted earlier, we had been speaking with regulatory bodies around the world and I committed to pursuing the most efficient but to be in the clinical program yeah.

This quarter, we must central phase one materials are finalizing the three bucks a month and remain on track to submit our I already or are you the equivalent see this year.

As previously shared the phase one trial will be a single ascending dose study easier patient intended to assess the safety of DNA 21.

He made a rating observable tune Biomarkers, we would also be able to evaluate that TVT body money during their decreased it circulating T ideal.

We aim to release the finalize phase one study design prior to study started expected in the second half of these yes.

Well this remains subject to the impact of Colby 19 on regulators and Pinnacle trial sites. We will continue to carefully monitor these conditions to ensure patient safety.

Laura Sepp: Thank you very much. We aim to release the finalized Phase I study design prior to the study start, expected in the second half of this year. While this remains subject to the impact of COVID-19 on regulators and clinical trial sites, we will continue to carefully monitor these conditions to ensure patient safety. We're very excited about this program, and our key opinion leader feedback indicates there is a great deal of enthusiasm about a potentially curative treatment for ADTR. Of note, MDLA-2001 is anticipated to be the first systemically delivered CRISPR-Cas9 therapy to enter the clinic, and it is being developed as part of our collaboration with Regeneron, with Intellia as the lead party. Now moving on to our next in vivo program in development for the treatment of HAE. HAE is a rare genetic disease characterized by recurring, painful, and unpredictable edema in various parts of the body. Most patients with HAE have a C1 esterase inhibitor deficiency, resulting in unregulated release and buildup of bradykinin, which in turn mediates vascular permeability and painful swelling. The disease affects about 1 in 50,000 people and can be fatal in certain cases.

We're very excited about this program and I want to European either feedback indicates they said grade dealer enthusiasm about potentially good. These treatments were 80 T R.

Oh no NPL may 21 is anticipated to be this first systemic you didn't ever CRISPR definitely to beat to enter the clinic.

And is being developed as far to follow collaboration with Regeneron, we didn't sound yeah, absolutely pardon.

Now moving on to our next level program in development for the treatment H.A.

Hmm is a rare genetic disease characterized maybe carrying painful unpredictable, indiana in various parts of the Bobby.

Most patients with 18 hobbies seem like it's great to see if it's a deficiency we sold the only when they then we need and build up that decline in which in turn mediates bucks and the permeability and painful Charlie.

Did you see I think about one is 50, so some people and can be say, though in certain cases.

Well, the acute and both we'd like to therapies for HM the treatment burden in the station you still significant.

With this program, we entolimod called the cable TV one gene. So we do that's my Kallikrein UHDTV broadband access ready Canyon production, we sold the H.T. attacks.

We they need to K MTV my Midcoast to be so that's your lunch with pre clinically deficiency appeared to have no known kelsen pets.

Laura Sepp: While there are acute and prophylactic therapies for HAE, the treatment burden of patients is still significant. With this program, we aim to knock out the KLKB1 gene to reduce plasma calicrine activity to prevent excess radicline production resulting in HA attacks. We believe KLKV1 knockout to be safe, as humans with precolicone deficiency appear to have no known health effects.

You know they show inhibition of Polychronic TV basically anybody they did approach source thinking HM.

Today, we're pleased to share additional brevini delayed that choice, that's not going to be kind of propylene activity reductions sustained through six months. Following a single dose Norman go in non human Primate study.

Laura Sepp: In addition, innovation of calicolectivity is a clinically validated approach towards treating HAE. Today, we're pleased to share additional durability data showing plasma can become protein and activity reduction sustained through six months following a single dose in an ongoing non-human primate study. We're encouraged by these results as they show that we can achieve levels of plasma glycolytic activity reductions expected to be clinically efficacious. Based on these results and other data, we're excited to nominate our third development candidate today, MDLA-2002, for the treatment of HAE. Our rapid and efficient path to selecting our HAE development candidate builds on the foundation developed for our ATTR program, demonstrating the strength of our modular approach. We have recently begun IND enabling activities for MDLA 2002 and plan to submit an IND or IND equivalent in the second half of 2021.

We're encouraged by these results as they show that we can achieve levels I smoke and he couldn't activity, we've actually expected to be clinically efficacious.

Based on these results another data we're excited to nominate I would start development candidate today and delayed twin owed to hold the treatment HM.

Other rapid and efficient, but the selecting our H E. B economy can do they built from the foundation would've been up for I were 80 their program demonstrating the strength of our mode or approach.

We'd have they seem to be done I and enabling a tbds <unk> NGL H one N. Two I'm glad to submit an I.N.V. I, India equivalent to the second half of 2021.

We look forward to sharing additional data on H.I.E. at the American Society of gene and cell therapy, I only be taking place virtually next week.

Switching now to our ex vivo affords me on oncology.

Laura Sepp: We look forward to sharing additional data on HAE at the American Society of Gene and Cell Therapy annual meeting taking place virtually next week. Switching now to our ex vivo efforts in immunoncology. At Intellia, we employ a TCR-based approach for adoptive T cell therapy. PCRs, unlike CAR-T, can target a much broader set of targets, including both surface and intracellular tumor antigens. As John mentioned, our focus is to engineer T-lymphocytes that retain normal cell physiology. By identifying a high affinity natural TCR and applying our proprietary T-cell engineering process, we're designing a cell product that closely mimics the natural biology of T-cells to attack tumor cells. As shown at the Keystone Symposium in February, we applied this approach to identify NTLA-5001, our engineered T-cell therapy development candidate for the treatment of AML. It targets the Worms Tumor 1, or WT1, antigen, which is overexpressed in over 90% of AML patients, regardless of driver mutations and disease subtypes. At Keystone, we had light lighted these attributes of MTLA-5001. First, it contains a naturally occurring TCR. This DCR is a modified, high-affinity, and sourced from Celtic honor to

At least 10, yeah, we employ it PCR based approach for adoptive T cell therapy.

CCRC. Unlike her teams come targets in much better understood the strongest including both surface and you just said when they're tumor antigens.

As John mentioned, our focus is the engineered T lymphocytes that we think normal sociology.

I, even be fine the highest finished the naturals DCR on applying our proprietary Cseven engineering process, what beside me. So for all that that's close mimics the natural biology of T cells, so what that tumor cells.

Actually almost the Keystone symposia in February we apply this approach to identify India makes you feel one I work engineered T cell therapy, but I mean can do they for the treatment Hmm.

It targets the bones July one or WT, one antigen, which is over express and over 90% Oh, no patients regardless of driver mutations and D.C. sub types.

It's Keystone, we had laid that these attributes and delay 50 or one.

First it contains naturally occurring Pcr.

Ms TCR, some multi side hi, if anything and so some healthy to honor to me my Swissqual seemed to TCT.

Laura Sepp: Second, the TCR binds to a novel WT1 epitope efficiently processed by the tumor protosome and presented by AML-BLAST. Third, our proprietary engineering process achieves greater than 98% removal of endogenous TCRs from nearly all T-cells to create a blank slate for the efficient insertion of the therapeutic TCR. This results in a T-cell product with high TCR expression, potency, and specificity. This represents a significant improvement over alternative TCR approaches where the native TCR is either partially removed or not removed at all, creating a heterogeneous T-cell product with not only reduced activity but also unpredictable specificity resulting from mispairing between alpha and beta chains of endogenous and therapeutic TCRs. We look forward to presenting additional data next week.

They come mid this year to binds to a noble WT, one epitope efficiently purchases made in tumor process and be some but I am not less.

Third our proprietary engineering process achieved greater than 98% local often don't you must D.C. ours. So nearly all d. so to create the blends late fourth efficiency insertion of this and I get the PCR.

These results the diesel brought up high teens share expansion both in C on specificity.

This represents a significant improvement over alternative TCR approaches one of the native TCR east either partially I wouldn't rule pardon up anymore, that's all creating it hits a genius diesel product.

Not only do we use a baby, but also unpredictable and specificity insulting from these between <unk> and there's a change of endogenous on therapeutic TCR.

We look forward to personally these additional data next week at S.G. Cds I know maybe on an important brlsix advancements in other words, so there's a new platform.

Laura Sepp: at ASGCT's annual meeting on an important process advancement in our cell engineering platform. We will show highly efficient editing of multiple genes with levels of translocations indistinguishable from background levels and favorable sole product attributes including high viability and expansion potential. Notably, we have incorporated this improved diesel engineering process into NTLA-5001.

We will show highly efficient editing multiple genes with levels of translocations indistinguishable from micro level and favorable sold product attributes, including cyber liability and expansion potential.

No. It doesn't mean, we have incorporated these Hebrew diesel engine you pulses into MTN I don't want.

In preparation for the blended we continued to like fund I IND, enabling activities, including crosses the phenomenon in support of kidney goat T cell lung function.

Laura Sepp: In preparation for the clinic, we continue to advance IMD enabling activities, including process development in support of clinical T-cell manufacturing. We remain on track to submit an IMD or IND equivalent in the first half of next year. Looking more broadly at the AML landscape, while treatments developed over the past several years have led to improved response rates, long-term outcomes continue to be poor. Overall, 5-year survival remains below 30%.

We remain on track to submit an I.M.B. I, India equivalent to the first half of next year.

Looking more broadly I am a landscape was created might develop over the past several years have led to improved response rates lung sort of outcomes continued to be poor.

Overall five years from Bible remains below 30%.

Laura Sepp: Our hope is that NTLA-50.01 will deliver a well-tolerated treatment that improves long-term outcomes for ANL patients regardless of the mutation background of their underlying leukemia. Additionally, as we've noted in the past, WT1 is overexpressed across many tumor types. As such, we're actively evaluating the potential to use the same WT1 TCR in multiple solid tumors. Outside of our wholly-owned ex vivo efforts, the FDA has accepted Novartis IMD applications for OTQ923, a CRISPR-Cas9-based engineered cell therapy born out of our research collaboration in developing sickle cell disease. We're pleased to share this important milestone, as this will be the first XBO application of our technology to be evaluated in patients, and we believe this program will provide important validation for our platform.

I would hope he said no delay 50, or one will deliver a well tolerated treatment that improves loans or outcomes for patients regardless of the mutation background Oh, there on the line looking.

Additionally, as we've noted in the past WT one is over express across many tumor types, such we're actively evaluating the potential to use the same WT, one PCR multiple solid tumors.

Outside of other wholly own ex vivo efforts. The F.D.A. has except that no Barclays I in the application for OTI Q 920 see it principally guests nine based medium cell therapy, both out of our research collaboration in development for CECO sell these.

Yes.

We're pleased to show this important milestone as this will be the first ex vivo application of our technology to eat everyone would any basins and we believe this program will provide important validation for our platform.

Finally, we continue to maintain his tongue research and James leveraging our multiple platforms to elaborate or the next wave of finished goods coming.

Laura Sepp: Finally, we continue to maintain a strong research engine, leveraging our modular platform to deliver the next wave of clinical candidates. These research programs apply our various genome editing and delivery capabilities across a variety of diseases, including hemophilia B, alpha 1 and beta trypsin deficiency, and others. With that, I would like to now hand over the call to Glenn, who will provide an overview of our first quarter 2020 financial results.

These research programs apply our various genome editing and delivery capabilities across a variety of Pcs is due to the hemophilia B Alpha one antitrypsin efficiency and others.

With that I would like to know how or what are the cold to Glenn Cohen provides an overview of our first quarter 2020, <unk> financial results.

Thank you Laura and good morning, and tell you remains in a strong financial position as we advance our pipeline.

Glenn G. Goddard: Thank you, Laura, and good morning. Intellia remains in a strong financial position as we advance our pipeline. Our cash, cash equivalents, and marketable securities as of March 31st, 2020 were $250.3 million, compared to $284.5 million as of December 31st, 2019. The decrease was mainly due to cash used to fund operations of approximately $40 million, which was offset in part by $4.5 million of net proceeds raised from the company's at-the-market offerings, $1 million of funding received under the Novartis collaboration, and $0.3 million in proceeds from Our collaboration revenue was $12.9 million for the first quarter of 2020 compared to $10.4 million for the same period in 2019. The increase in collaboration revenue in 2020 was mainly driven by the $5 million milestone payment earned from Novartis for the IND submission of OTQ-923.

Our cash cash equivalents marketable securities as of March 31st 2020.

For 250.3 million.

Compared to 284.5 billion as of December 31st 2019.

The decrease was mainly due to cash used to fund operations.

Approximately 40 million, which was offset in part by 4.5 million of debt proceeds raised from the company's aftermarket offerings.

1 billion of funding received under the Novartis collaboration in point Threemillion and proceeds from employee base talk plans.

Our collaboration revenue was 12.9 million for the first quarter.

2020, compared to 10.4 million for the same period in 2019.

The increase in collaboration revenue in 2020 was mainly driven by the 5 million dollar milestone payment earned from Novartis, but the R&D submission Oh TQ nine to three.

R&D expenses were 34.7 million for the first quarter of 2020 compared to 23.7 million at the same period in 2019.

Glenn G. Goddard: Our R&D expenses were $34.7 million for the first quarter of 2020, compared to $23.7 million for the same period in 2019. This increase was mainly due to the advancements of our LEAD programs, research personnel growth to support these programs, as well as our expansion of the development organization. Our G&A expenses were $11.3 million for the first quarter compared to $10.5 million for the same period in 2019. This increase was mainly driven by an increase in intellectual property-related expenses due to increased patent activity. 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. Thanks.

This increase was mainly due to the advancement of our lead programs research personnel growth to support these programs.

As well as our expansion of the development organization.

Our general expenses were 11.3 million for the first quarter.

Compared to 10.5 million for the same period in 2019.

The increase was mainly driven by an increase in no actual property related expenses due to increased patent activity.

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 in corporate updates.

Thanks, Glenn and Laura for the updates.

Before concluding the call I'm excited to introduce Dr., David let wall doesn't tell you its new Chief Medical Officer.

John M. Leonard: Thank you Glenn and Laura for the update. Before concluding the call, I'm excited to introduce Dr. David Lebwohl as Intellia's new Chief Medical Officer. David recently joined us from Sema Therapeutics, where he was chief medical officer. He served in roles of increasing drug development responsibility over a 16-year tenure at Novartis, most recently as senior vice president and global head of the CAR-T team, where he developed and launched Chimriah and the multi-indication cancer blockbuster Afinitol. He's one in a handful of R&D leaders who have successfully brought a novel engineered cell therapy product through FDA approval and to patients. David's deep development expertise in rare diseases, oncology, and engineered cell therapy is a huge asset and complements the scientific capability and talent we have amassed at Intellia. We're incredibly fortunate to welcome David to our team and to gain his medical and clinical development expertise, particularly in injury

David recently joined US from Summit Therapeutics, where he was chief Medical Officer.

Certain roles of increasing drug development responsibility over 16 year tenure at Novartis. Most recently as senior Vice President and global head of the car teaching, where he developed and watched them right and the multi indication cancer blockbuster affinity.

He's one in a handful of R&D leaders, who have successfully brought a novel engineered cell therapy products throughout the approval at the patients <unk> deep development expertise in rare diseases oncology and engineered cell therapy for a huge assets and complement the scientific capability and talent, we have a mastered until you.

We're incredibly fortunate to welcome David toward team and again as medical in clinical development expertise, particularly uninjured cell therapies.

And of course this comes at a critical juncture in the company's growth we continue to make rapid progress across your emerging pipeline for severe genetic diseases and cancer as we prepare until a 21 to enter the clinic with other programs poised to follow.

He ahead the balance of 2020 and beyond we have several important milestones upcoming in summary.

John M. Leonard: And, of course, this comes at a critical juncture in the company's growth. We continue to make rapid progress across our emerging pipeline for severe genetic diseases and cancer as we prepare NTLA-2001 to enter the clinic, with other programs poised to follow. Looking ahead to the balance of 2020 and beyond, we have several important milestones ahead. In summary. For NTLA 2001, we plan to submit our IND or IND equivalent in the middle of this year, and, current conditions permitting, plan to dose our first ATTR patient in the second half. For NTLA-5001, we continue to advance IND-enabling activities and anticipate submitting an IND or IND-equivalent in the first half of next year, and for our newest development candidate, NTLA-2002, we expect to submit an Again, I'd like to thank you all for tuning into the call today. We will now open the line to any questions. Operator.

For until a 21, we plan to submit or I into your eye in the equivalent to the middle of this year and current conditions permitting plan to dose or first aid TTR patients and the second half of the year.

Brent, Chile, 50, or one we continue advance I, India, enabling activities and anticipate submitting a 90 Orion de equivalent the first half of next year.

And for our newest development candidate until late 20th true, we expect to submit an eye in the Orion de equivalent application in the second half of next year.

Additionally, we look forward to presented preclinical data supporting certain programs some platform improvements at the S. GCG annual meeting next week.

Again I'd like to thank you all for tuning into the call today, we will now open the line to any questions operator.

We will now begin the question and answer session to ask a question you May Press Star then one on your Touchtone phone.

If you are using a speakerphone please pick up your handset before pressing the keys.

To withdraw your question. Please press Star then too.

At this time, we will pause momentarily to assemble a roster.

The first question comes from Steve sheet House of Raymond James. Please go ahead.

Yeah, Hi, this is a ton we're going to go on for Steve see his house and our first question is maybe for our Jose in terms of the oral argument for the I.P. artists catch automate team could you remind us about the potential set of outcomes for the hearing and then maybe the general timeline for this case in terms of the potential resolution.

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. To withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. The first question comes from Steve Seedhouse of Raymond James. Please go ahead.

I can say you Watch act that Yep Yep sure a good morning, so the potential outcomes at this point, obviously, there's a motion by the brode seeking to especially terminate the interference if that were to happen that.

Do you see side would have his current set of patents that cover single guide or in any setting.

Timor Revance: Yes, hi, this is Timor Revance on behalf of Steve Seedhouse, and our first question is maybe for Jose, in terms of the oral argument for the IPR that's scheduled on May 18th, could you remind us about the potential set of outcomes for the hearing and then maybe the general timeline for this case in terms of the potential resolution?

And then the road would have for now are subject to appeals the you periodic.

Package.

The we believe obviously that likely outcomes are will move forward.

To the second phase.

A decision on devotions is likely to occur within three months as usually the timeline, although we can't guarantee how long.

Jose Rivera: I'll say you want to,

Joseph John: ..

Joseph John: Sure.

Joseph John: Good morning. So the potential outcomes at this point, obviously, there's a motion by DeBrogue seeking to essentially terminate the interference. If that were to happen, then the UC side would have its current set of patents that cover single guide in any setting, and then the Broad would have, for now, subject to appeals. The eukaryotic patents. We believe, obviously, that the likely outcome...

And then the second phase would happen after that and that's where it better ship would be decided.

Okay. Thank you and then or second question about be HCR program. I think you mentioned potential delays due to covert 19 could you just provide any color.

In terms of the impact on they TTR study.

Is it more of an impact just on a hospital inpatient arrangement a it sounds like you have the supply ready to go Oh, so any color would be appreciated. Thank you.

Joseph John: and likely Alchemist that will move forward.

Joseph John: to the second phase. A decision on the motions is likely to occur within three months. That's usually the timeline, although we can't guarantee how long. And then the second phase would happen after that, and that's where inventorship would be decided.

Yeah. This is John just to be clear, we're not saying that we know there's a delay.

In fact.

Everything that we can control on our end is on time, which pushes our guidance that yeah. We will have the regulatory applications in and we fully expect to be dosing patients before the end of year.

John M. Leonard: Okay, thank you. And then our second question about the ATTR program. I think you mentioned potential delays due to COVID-19. Could you just provide any color in terms of the impact on the ATTR study? Is it more of an impact just on hospital and patient arrangements?

Where things get beyond our control and would be later this year, we have other waves of co bids that interfere with.

Individual clinical sites for the transit or patients to them.

But we're very very carefully engaging with the clinics to make sure that sort of that's a of our ability we're able to avoid that not they kind of in eventuality.

John M. Leonard: It sounds like you have the supply ready to go. So any color would be appreciated. Thank you.

Okay. Thank you very much.

The next question comes from GE not wing of Barclays. Please go ahead.

John M. Leonard: This is John. Just to be clear, we're not saying that we know there's a delay. In fact, everything that we can control on our end is on time, which is our guidance that we will have the regulatory applications in and we fully expect to be dosing patients before the end of the year, where things get beyond our control and would be later this year if we have other waves of COVID that interfere with individual clinical sites or the transit of patients to them but we're very very carefully engaging with the clinics to make sure that to the best of our ability we're able to avoid that that kind of an eventuality.

[laughter] Hi, this is a gene column for July one I have a two question to start my first question. So for your eight TTR program since they're going to be a the first in vivo Andy application for CRISPR Casnine.

Technology do you expect actually X for scrutiny from the FDA or we would you share with that's a you know a wouldn't the R&D clearly when the and it would be the I know when you well file.

And Ah so since you know the banks when is that there's several hold before so that's my first question second question about the edge a program one additional steps you need to take actually before you I Indeed submission.

John M. Leonard: Okay, thank you very much.

Second quarter of a 2021.

Yeah. So thank you for the question first for TTR.

Gena Wang: The next question comes from Gena Wang of Barclays. Please go ahead.

Extra scrutiny I I guess I think of it as applying the appropriate scrutiny, which is the basis of how we approach the FDA and.

Jun Tao: Hi, this is Jun Tao from 4G91. I have two questions to start. My first question is for your ATTR program, since they're going to be the first in vivo and the application for CRISPR-Cas9 technology, do you expect extra scrutiny from the FDA? Would you share with us when the IND is cleared, when the IND will be cleared, and when you will file? And so since, you know, the background is that there are several holes before. So that's my first question. Second question about the H-A-E program. What additional steps do you need to take, actually, before your IND submission in the second quarter of 2021?

The various regulatory engagements that we have with them as as we start the regulatory process in particular therapy R&D meetings part of this is to make sure that we about share an understanding of the nature of the data that we need to present. So we can go and generate that for them. So that there'll be an adequate package for them to do.

Determine that we're able to proceed that's true for all regulatory agencies, whether it's yeah, hey, rich or or agency is outside the U.S. So we think we're addressing their questions.

I would say that.

John M. Leonard: Yeah, so thank you for the question. First for TTR.

In most cases, what one needs to generate largely overlaps what is true for other products as well, there's not a unique set of circumstances, where data that one needs to generate for these sorts of products. So we think we're gonna be in a position to address or what they need to.

John M. Leonard: Extra scrutiny. I guess I think of it as applying the appropriate scrutiny, which is the basis of how we approach the FDA and the various regulatory engagements that we have with them. As we start the regulatory process, in particular with our PID meetings, part of this is to make sure that we have a shared understanding of the nature of the data that we need to present so we can go and generate that for them so that there'll be an adequate package for them to determine that we're able to proceed. That's true for all regulatory agencies, whether it's the FDA or agencies outside the U.S. So we think we're addressing their questions. I would say that, in most cases, what one needs to generate largely overlaps what is true for other products as well. There is not a unique set of circumstances or data that one needs to generate for these sorts of products.

Make a determination.

I think you asked when we would announce a where we are what the program or our plan is to announce a once were up and running and we've cleared the regulatory process and that's.

Our plan for an hour and certainly will give good insight as to what the protocol is and how we're going to approach these patients.

With respect to ha E or what are the additional steps or I mean, we just announced development candidates, we're moving very expeditiously and appropriately to the clinic again. This is generating these standards sort of regulatory information completing the necessary manufacturing and Tox work.

John M. Leonard: So we think we're going to be in a position to address what they need to make a determination. I think you asked when we would announce where we are with the program. Our plan is to announce once we're up and running and we've cleared the regulatory process, and that's our plan for now. Certainly, we'll give good insight as to what the protocol is and how we're going to approach these patients.

We learned how to do that pretty effectively now with our first go out a TTR and we're hoping to leverage all the insights that we've gained not only from manufacturing toxicological work and ultimately perhaps even from the clinical work that we're dealing with TTR. So.

John M. Leonard: With respect to HAE, what are the additional steps? I mean, we just announced the development candidates. We're moving very expeditiously and appropriately to the clinic. Again, this is generating the standard sort of regulatory information and completing the necessary manufacturing and toxicology work. I think we've learned how to do that pretty effectively now with our first go at a TTR, and we're hoping to leverage all the insights that we've gained, not only from manufacturing but from the toxicological work, and ultimately, perhaps even from the clinical work that we're doing with TTR. So we're very excited about this application of our modular approach as we move forward.

We're very excited about this application of our modular approach as we move forward.

That's great just so I have a one quick follow up for they and Novartis collaboration programs in a C. D could you remind us the modification you made.

Yes, so just to be clear Oh. This is novartis is program, we'd like to think of it is intellia inside a we've done the basic work on the discovery side on a collaborative basis with them. We've determined key elements for the data package that went to the FDA.

Hey, but the particulars of how they the gene is edited into development program itself a applies to novartis, so there'd be better position to describe that work and how the progressing it.

Okay, great. Thank you very much.

The next question comes from Maury Raycroft of Jefferies. Please go ahead.

Hi, good morning, and thanks for taking my questions I'm not seeing a a TTR title at Ace you see as GCP. So just wondering if you can provide the latest status update on NHP is treated with 2001 I think your last update was with a follow up to 52 weeks. So how long is follow up today and our team.

John M. Leonard: That's great. So I have one quick follow-up. For the Novartis collaboration program in SCD, could you remind us of the change you made?

John M. Leonard: Yeah, so just to be clear, this is Novartis's program. We like to think of it as Intellia inside.

John M. Leonard: We've done the basic work on the discovery side on a collaborative basis with them. We've determined key elements for the data package that went to the FDA. But the particulars of how the gene is edited in the development program apply to Novartis, so they're in a better position to describe that work and how the progress has been made.

<unk> reduction so flat.

Oh, Yeah, there's no additional data that Oh, we're presenting and are essentially that's where we've got the experiment at this point so that was the duration for work.

Got it Okay and then congrats on the 2000 to update I'm, just wondering if you're seeing any phenotype in the CNH piece that have been treated so far and is there anything unique you're seeing relative to your treated TTR in age fees.

John M. Leonard: Okay, great. Thank you very much.

Maurice Thomas Raycroft: The next question comes from Maurice Raycroft of Jeffreys. Please go ahead. Hi, good morning and thanks for taking my questions. I'm not seeing a TTR title at ASGCT, so just wondering if you could provide the latest status update on NHPs treated with 2001.

[noise] up more it will look very closely at these animals course, you know these are exaggerated pharmacology studies for one can try to determine any sort of readily observable observable effect and today, we'd see nothing.

John M. Leonard: I think your last update was with...

Great. Okay, and then last question.

John M. Leonard: Thank you all for joining us today.

It sounds like it is easy to you will see some data on improved T cell engineering, and Lori talked a little of it a little bit about the proprietary engineering process for five years or a one I guess, how much of that will be disclosed at age GCT, what should we focus on and then for the program can you provide if you specifics around.

John M. Leonard: Yeah, there's no additional data that we're presenting, and essentially, that's where we stopped the experiment at this point, so that was the duration of the work.

John M. Leonard: Got it. Okay. And then congrats on the 2002 update. I'm just wondering if you're seeing any phenotypes in the NHPs that have been treated so far, and is there anything unique you're seeing relative to your treated PTRNHPs?

Manufacturing such as the number of days it'll take to process cells from start to finish.

Yeah, So with respect to the editing. This is this is work that we're very very excited about and what will show or the performance. So those cells in terms of how well, we edit them how well the cells behave.

John M. Leonard: More importantly, we look very closely at these animals, of course, you know, these are exaggerated pharmacology studies where one can try to determine any sort of readily observable effect, and to date, we've seen nothing.

And importantly, the ability of those cells to robustly divide and in fact far exceed the division and multiplication expansion that typically takes place with cells that are edited and the standard fashion. We think that that is a hugely important for delta their performance somebody cells.

John M. Leonard: Great, okay. And the last question, it sounds like at ASGCT we'll see some data on improved T-cell engineering, and Laura talked a little bit about the proprietary engineering process for 5001. I guess how much of that will be disclosed at ASGCT? What should we focus on? And then for the program, can you provide a few specifics around manufacturing, such as the number of days it'll take to process cells from start to finish?

But.

John M. Leonard: Yeah, so with respect to the editing, this is work that we're very, very excited about, and what we'll show is the performance of those cells in terms of how well we edit them, how well the cells behave, and importantly, the ability of those cells to robustly divide and, in fact, far exceed the division and multiplication expansion that typically takes place with cells that are edited in the standard fashion. We think that that is hugely important for the ultimate performance of these cells, but equally important and something I can't stress enough is the ability to serially edit and have a level of translocations that's essentially indistinguishable from background levels. We think that that by itself is going to really enable our ability to have multiple edits in these cells.

John M. Leonard: And when you think about where one might want to go, not just for the first product, which is for the treatment of AML, but as we think about other indications and other modifications that we want to make, the ability to make a multiplicity of changes and not induce translocation is something that we think essentially puts very few limits on where we can go. So, very excited. In terms of how we do it, well, that's work we've done and something that is proprietary, but I would say this: there are multiple steps along the way that one can look at very carefully and improve. And we've tried to do that each step of the way. So, you'll see the data and the performance of the cells, and I think that'll be

John M. Leonard: I got it. Well, we learned some of the process at ASGCT then, I guess.

John M. Leonard: Will some of the proprietary information come out at that point? No. Okay. Okay. Okay. The next question comes from Mani Foroohar of SVB Lyrinc. Please go ahead.

Rick Stephen Bienkowski: Hey, good morning everyone. This is Rick on the call for Mani.

John M. Leonard: Congratulations on all the progress. So first, I also wanted to touch on the timing for the upcoming dosing of the first ATTR patient in the 2001 study. So we know that clinical trials have been slowed down across the board due to COVID-19, and this is mostly due to hospitals not being able to perform elective procedures. Could you comment specifically on the clinical trial sites that are planned for the 2001 study if these sites are currently performing elective procedures or if there are any timelines in place for restarting these?

John M. Leonard: I can't speak to what sites are doing with their other programs. We focus on the work that we're going to do. With respect to the timing, we've given guidance and are continuing to provide that guidance that we expect to be dosing patients before the end of this year. I think one point to take away is that programs have been most effective, ones that are currently in the clinic today. And in some respects, where we are, I think, is somewhat advantageous, being on the cusp of beginning clinical work, where we can think very carefully about how to navigate this process, look at, you know, the logistical challenges that have been presented by the virus, look at how sites are dealing with it, not do it on the fly but come prepared with whatever the circumstances are. So, again, expect to be dosing patients before the end of the year, and, you know, the particular clinics, et cetera, are information that we'll provide down the road.

To be dosing patients before the end of year and you know the particular clinics et cetera information that will provide down the road.

Alright, great. That's a that's very helpful.

I know the follow up question for the H.I.E. program.

So we saw the you know A.S.D.C.T. abstracts, and the earlier keys, some presentations that you're able to achieve.

90% knocked down and plasma Collie crying and my son nonhuman primates. So are there any internal models that would make a prediction for what kind of effect. This would have on H.A. attack <unk> I'm, just trying to get a sense of what the target profile for the genetic thing product would be compared to the current standard of care.

Yeah. Thanks for the question you know what we try to do is benchmark off of what's been done in human studies using other modalities and so when you think about Kallikrein and it's inhibition antibiotic place that we look too.

John M. Leonard: Great, that's very helpful. I do have a follow-up question about the HAE program. So we saw in the ASGCP abstracts and the earlier Keystone presentations that you're able to achieve a 90% knockdown in plasma collycrine in mice and non-human primates. So are there any internal models that would make a prediction for what kind of effect this would have on the HAE attack rate? I'm just trying to get a sense of what the target profile for the gene editing product would be compared to the current standard of care.

And.

Zero I think is a useful benchmark, where when looks at degrees of inhibitions and then the common at a pack rate results. So we expect to be competitive with those kinds of attack rich and perhaps more so certainly our objective to provide a one and done approach that.

Has zero order pharmacokinetics meeting invariant.

And that has attacked rates that are we hope below those already achieved.

John M. Leonard: Yeah, thanks for the question. You know, what we try to do is benchmark it against what's been done in human studies using other modalities. And so when you think about calocrine and its inhibition, antibodies are the place that we look to. And TAC0, I think, is a useful benchmark where one looks at degrees of inhibition and then the concomitant attack rate that results. So we expect to be competitive with those kinds of attack rates and perhaps more so. Certainly, our objective is to provide a one and done approach that has zero order pharmacokinetics, meaning invariant, and that has attack rates that are, we hope, below those already achieved.

Great. Thank you and we're looking forward to S.T.C.P. presentations.

Thank you.

The next question comes from my two Kumar of R.W. Baird. Please go ahead.

[noise] Hey, guys. Thanks for taking our question so kind of following Monday can it can.

Considerations that the clinical execution plan for 2000, wanting T.T.R. to what extent can be kind of management, a patient and the clinical trial being done like robo. They can you do get a bloody collection from home do kind of safety intolerability lessons from homes versus having them come on site.

[noise] Yeah. Those are important questions my do in in all parts of things that were working through again back to the earlier question. We got in terms of being in a position to engineers. Some of these ways of filing patients, we're taking that into consideration.

John M. Leonard: Great, thank you. And we're looking forward to the ASGTT presentations.

John M. Leonard: Thank you.

Matu Kumar: The next question comes from Matu Kumar of RW Baird. Please go ahead.

As we go.

John M. Leonard: Hey guys, thanks for taking our questions. So kind of following on the kind of considerations of the clinical execution plan for 2001 and TTR, to what extent can the kind of management of patients in the clinical trial be done like remotely? Can you do blood collection from home, do kind of safety and tolerability assessments from home versus having them come on site?

There's there's a lot that we think we can do obviously you know in a phase one study there is a point where patients are confined in the clinic and so it's hard to do that virtually [noise], but after that I think there's lots of opportunities to go and follows patience remotely. So we hope to engineer that in and again, we're trying to learn.

From those have gone before us.

It kind of falling from dad thinking about the assessment strategy into phase one does <unk> kind of your ability to look at in Plano beyond serum TTR level, so things like Paulina drop in the in planes or cardio my up at the end planes that are.

John M. Leonard: Yeah, those are important questions, Madhu, and all part of the things that we're working through. Again, back to the earlier question we got in terms of being in a position to engineer some of these ways of following patients. We're taking that into consideration as we go. There's a lot that we think we can do. Obviously, you know, in a phase one study, there is a point where patients are confined to the clinic. And so it's hard to do that virtually. But after that, I think there are lots of opportunities to go and follow those patients remotely. So we hope to engineer that in. And again,

There were would require like pretty extensive clinical business or at least some kind of in personal clinical assessment.

It's not apparent to me how that would influence us I mean, obviously, we don't want patients to become ill. During the course of study. So you know that was part of the discussion in terms of trends that have patience to and from the clinic and making sure that patients when they come in or otherwise well.

But the the biggest part of what we're looking for in our very first study is safety in the extent of teach yard knocked down which is an object of read out that we get with a simple blood draw. After a a few weeks of observation. So I think.

John M. Leonard: And kind of following from that, thinking about the assessment.

John M. Leonard: Phase 1. Does COVID impact your ability to look at endpoints beyond serum TTR levels, so things like polyneuropathy endpoints or cardiomyopathy endpoints that are, that would require pretty extensive clinical visits or at least some kind of in-person clinical assessment?

<unk>, what we're looking for in phase one should be readily.

And then finally moved when it had the phase one trial is there any possibility of kind of subsequent <unk> patients that kind of early or some tear everything goes to the cutting get TCR down to that kind of target profile for TTR suppression, you're looking for.

John M. Leonard: It's not apparent to me how that would influence this. I mean, obviously, we don't want patients to become ill during the course of the study. So, you know, that was part of the discussion in terms of transporting patients to and from the clinic and making sure that patients, when they come in, are otherwise well. But the biggest part of what we're looking for in our very first study is safety in the extent of TTR knockdown, which is an objective readout that we get with a simple blood draw after a few weeks of observation. So, I think, you know, what we're looking for in phase one should be readily observed.

Yeah, I know it's important question.

And it comes from the notion that this is a single ascending dose study, where one starts a lower in the therapeutic index and and those fines as as we ascend obviously the objective is to do that with a few as number of patients fewer number of those escalations possible, but it is higher.

Possible that that first sets of patience, which we would expect to be small would have the sub therapeutic those in the phase. One study itself. They are at least that's currently planned they would not be subject to reducing but in the course of the larger program. Once we find those therapeutic though says we would definitely try.

John M. Leonard: And then finally, thinking about the Phase 1 trial, is there any possibility of kind of subsequent dosing of patients at kind of earlier sub-therapeutic doses to kind of get TTR down to the kind of target profile for TTR suppression you're looking for?

To make provisions for patients to come back that's that's all work a underway.

Okay. Thanks, very much by the way and that was really great Intellia inside that's classic.

Okay. Thank you.

The next question comes from Tony Butler of Rough capital. Please go ahead.

That's good morning, John just want to follow one on that series of questions with respect to the to the clinical outcome of P. to your administration and the question really is.

John M. Leonard: It's an important question, and it comes from the notion that this is a single ascending dose study where one starts lower in the therapeutic index and increases the dose as we ascend. Obviously, the objective is to do that with the fewest number of patients, the fewest number of dose escalations possible, but it is entirely possible that that first set of patients, which we would expect to be small, would have a sub-therapeutic dose. In the phase one study itself, as currently planned, they would not be subject to re-dosing, but in the course of a larger program, once we find those therapeutic doses, we would definitely try to make provisions for patients to come back. That's all work underway.

You had alluded to some therapeutic doses, obviously in the ascending dose study understand that.

But as T.T.R. as a surrogate diminishes in senior.

How do you believe that that correlates with an improvement or potential improvement and peripheral neuropathy or or hydrocephalus or whatever the case may be clinically and I'm, making an assumption here and I'm asking you to to I'm sure you've given this truck.

<unk>, but but in in from from enough to gay perspective.

We do not have to demonstrate some level of improvement in those particular clinical markers, which which I think will be very important beyond that surrogate and and and I guess fall one to that is when when you get to a certain level that has and we spend the phase one which has an appropriate knocked down the too like.

John M. Leonard: Okay, thanks very much. And by the way, that was really great. Intellia, I'm sorry, that's class. Okay, thank you.

Tony Butler: The next question comes from Tony Butler of Roth Capital. Please go ahead.

Hi, how are you actually able to gauge whether or not that that might be appropriate dose to move forward because clinical you're not really sure that those particular <unk>. If you will will be totally abrogate. Thank you.

John M. Leonard: Yes, good morning. John, I just want to follow on that series of questions with respect to the clinical outcome of TTR administration, and the question really is, You had alluded to sub-therapeutic doses obviously in the ascending dose study, understand that, but as TTR as a surrogate diminishes in the serum, How do you believe that that correlates with an improvement, or potential improvement, in peripheral neuropathy, or hydrocephalus, or whatever the case may be, clinically, and I'm making an assumption here, and I'm asking you to, I'm sure you've given this tremendous thought, but in the end, from an FDA perspective, Would you not have to demonstrate some level of improvement in those particular clinical, which I think will be very important beyond that surrogate.

[noise] so Tony Thanks for the question [noise].

A couple of things wrapped up in that.

So first we we look to those who have gone before us who have demonstrated a tight link between T.T.R. knocked down levels and therapeutic outcomes, particularly with respect to polyneuropathy.

In here, we certainly look to El Nio them and the outstanding work that they've done and I own as a where with two different modalities that both lead to the same.

<unk> chemical outcome, which is a reduction teachey are they both see clinical improvement.

John M. Leonard: And I guess a follow-on to that is when you get to a certain level that has, at least in phase one, which has an appropriate knockdown that you like. How are you actually able to gauge whether or not that might be the appropriate dose to move forward because clinically you're not really sure that those particular neuropathies, if you will, will be totally abrogated? Thank you.

So.

When you think about from that standpoint, and and just thinking about the path physiology of the disease, which as in most cases and aberrant protein that is deposited in tissue.

I think the the treatment logic is clear.

John M. Leonard: So, Tony, thanks for the question. A couple of things wrapped up in that. First, we look to those who have gone before us, who have demonstrated a tight link between TTR knockdown levels and therapeutic outcomes, particularly with respect to polyneuropathy. Here, we certainly look to Al Nylum and the outstanding work that they've done, and Ionis, where there are two.

Is to reduce that protein so there's not a lot of discussion about that.

Utility however, teach your levels as a surrogate marker for drug approval as opposed to an indicator of what is a likely outcome or it's a different thing the regulatory agencies [noise] have not yet moved to make those reductions surrogate.

John M. Leonard: different modalities that both lead to the same chemical outcome, which is a reduction in TTR. So, when you think about it from that standpoint, and just think about the pathophysiology of the disease, which is, in most cases, an aberrant protein that is deposited in tissue, I think the treatment logic is clear. The idea is to reduce that protein, so there's not a lot of discussion about that. Utility, however, of TTR levels as a surrogate marker for drug approval, as opposed to an indicator of what is a likely outcome, is another thing. The regulatory agencies...

Caters that serve as the basis of <unk>. So you have to do the clinical work [noise].

Excuse me.

So again the idea is to find a dos and as was asked earlier, maybe even a second goes second treatment or application if necessary to get to those T.T.R. levels that we already know Ah argh associated with good therapeutic outcomes and to do.

That in a way that is highly competitive with taught what is already out there. So that in a nutshell is the logic that we are part of the program that would apply to <unk> and also cardio my let's say in I think.

John M. Leonard: have not yet moved to make those reductions. Surrogate indicators that serve as the basis of proof. So you have to do the clinical work.

You know here in this space, there's less complete information on the correlation of the extent there'll be improvement between teeter knocked down on the effect I've heard of my apathy, but that's accumulating and again, we feel that were well positions Ah because we're being taught by people who are a little bit of ahead.

John M. Leonard: So again, the idea is to find a dose, and, as was asked earlier, maybe even a second dose, a second treatment, or application if necessary, to get to those TTR levels that we already know are associated with good therapeutic outcomes and to do that in a way that is highly competitive with what is already out there. So that, in a nutshell, is the logic that we apply to the program.

US so that we can apply those learnings directly to our program and design a clinical study that we think would be highly likely to succeed and be very very efficient.

John M. Leonard: That would apply to polyneuropathy and also cardiomyopathy. And I think, you know, here in this space, there's less complete information on the correlation of the extent of the improvement between TTR knockdown and the effect of cardiomyopathy, but that's accumulating. And again, we feel that we're well-positioned because we're being taught by people who are a little bit ahead of us so that we can apply those learnings directly to our program and design a clinical study that we think would be highly likely to succeed and be very, very efficient.

Like a junk push it.

Sure.

And the last question today will come from J. Olson of Oppenheimer. Please go ahead.

Oh, Hey, congrats on the progress and think her taking the question maybe just to follow on a little bit two counties question. We have you had to moving 20 on into the clinic.

Can you comment on the potential value N.T. probing N.P. is it biomarker for a T.T.R. and whether or not you plan to to measure in <unk> isn't endpoint.

[noise] I I'm not in a position today to talk about that yet certainly.

Does relates to the questions at Tony's asking me in terms of the biochemical markers that we can measure and projecting from them likely clinical benefit.

Tony Butler: Thank you, John. I appreciate it.

Jay Olson: And the last question today will come from Jay Olson of Oppenheimer. Please go ahead.

John M. Leonard: Hey, congrats on the progress and thanks for taking the questions. Maybe just to follow on a little bit to Tony's question, as you look ahead to moving 2001 into the clinic, can you comment on the potential value of NT-ProBNP as a biomarker for ATTR and whether or not you plan to measure NT-ProBNP as an endpoint?

<unk> cardio my let's see where there's Ah you know an emerging story.

In terms of the relationship of actual Knockdowns too outcomes, Yeah, I I would start with the premise that we're gonna measure everything we can in the phase one studies to make sure that we have the most information possible and then of course, we would relate that to what the experts can gidus.

John M. Leonard: I'm not in a position today to talk about that yet. Certainly, and it does relate to the questions that Tony is asking me, in terms of the biochemical markers that we can measure and projecting from them likely clinical benefit, to cardiomyopathy, where there's, you know, an emerging story in terms of the relationship of actual knockdowns to outcomes. You know, I would start with the premise that we're going to measure everything we can in the phase one studies to make sure that we have the most information possible, and then, of course, we would relate that to what the experts can guide us in terms of its meaning and utility and relate it to whatever others have found as they proceed with their various knockdown programs. So I wouldn't base it solely on that again, but the basic logic here is about reducing protein, and I think that is going to be the first and foremost in our minds, and that is directly measurable, and you know that will be our primary guide.

In terms of its meaning of utility and related to whatever others have found as they proceed with her various knock down program. So I I wouldn't base it solely on that again the the basic.

Logic here it is about reducing approaching.

And I think that it's going to be the first and foremost in our minds and that is directly measurable in you know that will be our our our primary guide.

Great. Thank you and then maybe just on 20 or two I think you had you had six months of data and and H.P. isn't it [laughter] for your I.N.D. or do you plan to submit 12 months in the data.

[noise]. So [noise]. This is a model that shows the extent to the effect if you're asking the toxicological work that would be part of that program. That's distinct from the data that we presented so far and.

John M. Leonard: Great, thank you. And then maybe just in 2002, I think you said you had six months of data and NHP. Is that sufficient for your IND, or do you plan to submit 12 months of data?

Your question relates to how much we're going to be able to build off of prior work we've done from a toxicological basis.

John M. Leonard: So this is a model that shows the extent of the effect. If you're asking about the toxicological work that would be part of that program, that's distinct from the data that we've presented so far. And your question relates to how much we're going to be able to build off of prior work that we've done from a toxicological basis. And that is a point of some discussion as we proceed. So stay tuned.

And that is a point of some discussion as we proceed so state to him.

Great. Thanks again for taking the question looking ahead to it's easy to you and stay healthy.

Thank you too.

This concludes our question and answer session I would like to turn the conference back over to <unk> for any closing remarks.

<unk>. Thank you all for joining today's call him for your continued interest in support it before I get opinions on our progress hope everyone has a nice day.

Jay Olson: Great, thanks again for taking the questions, looking ahead to ASGC2, and stay healthy. Thank you, you too.

The conferences now concluded. Thank you for attending today's presentation you may now disconnect.

Lina Li: This concludes our question and answer session. I would like to turn the conference back over to Lina Li for any closing remarks.

Yeah.

[music].

Lina Li: Great, thanks Andrew. Thank you all for joining today's call and for your continued interest and support. We look forward to updating you on our progress. Hope everyone has a nice day.

Operator: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.