Q1 2021 Intellia Therapeutics Inc Earnings Call

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Izzy: Good morning. My name is Izzy, and I'll be a conference operator today. Welcome to the Antilia Therapeutics First Quarter 2021 Financial Results Conference Call.

Izzy: As a brief reminder, all participants are currently in a listen-only mode. If anyone requires operator assistance during the conference, please press Star Zero on your telephone keypad. Following formal remarks, we will open the call up for questions. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. I will now turn the conference over to Lena Lee, Director of Investor Relations and Intellia.

Joon So Lee: Thank you, and good morning, everyone. Welcome to Entelia's first quarter 2021 earnings call. Earlier today, the company issued a press release outlining the company's progress this quarter, as well as topics for the discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at InteliaTX.com. This call is being broadcast live, and a replay will also be archived on the company's website.

Good morning, My name is a day and I'll be a conference operator today welcome to the until you Therapeutics third quarter 2021 financial results Conference call.

Is it break from mines all phone participants are currently in a listen only mode.

If anyone require operator assistance during the conference. Please press star zero on your telephone keypad.

Following formal remarks, we'll open the call up for questions.

This conference is being recorded at the company's request.

And will be available on the company's website following the end of the call.

I will now turn the conference over to Lina Li Director of Investor Relations I can tell you.

John M. Leonard: At this time, I would like to take a minute to remind listeners that during this call, Intelli Management may make certain forward-looking statements and ask that you refer to our SEC filings available at sECD.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intelia undertakes no duty to update this information unless required by law. Joining me on the call today are Dr. John Leonard, Chief Executive Officer; Dr. David Levall, Chief Medical Officer; Dr. Laura Step Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer.

Please proceed.

Thank you operator, and good morning, everyone welcome to <unk> first quarter 2021 earnings call.

Earlier today, the company issued a press release outlining the Companys progress this quarter as well as topics further the discussion on today's call.

This release can be found on the investors and media section of <unk> website at <unk> Dot com.

This call is being broadcast live and a replay will also be archived on the company's website.

At this time I would like to take a minute to remind listeners that during this call and Telia management may make certain forward looking statements and ask that you refer to our SEC filings available on SEC Gov for a discussion of potential risks and uncertainties.

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

Joining me on the call today are Dr. John Leonard Chief Executive Officer, Dr. David Lebel, Chief Medical Officer, Dr. Laura Sepp, Lauren Dino Chief Scientific Officer, and Glenn Goddard, Our Chief Financial Officer for today's call John will start with the company's first quarter and recent business highlights followed by David who will provide an update on NGL a 'twenty on one clinical effort.

John M. Leonard: For today's call, John will start with the company's first quarter and recent business highlights, followed by David, who will provide an update on NTLA 201 clinical efforts. Laura will then recap the company's R&D progress, followed by Glenn's review of Intelli's financial results for the quarter. John will then make some closing remarks, and we will open the call for Q&A. With that, I will turn the call over to our CEO.

Laura will then recap the company's R&D progress followed by one's a review of <unk> financial results for the quarter. John will then make some closing remarks, and we will open the call for Q&A.

Let me turn the call over to our CEO John.

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

Thank you Leanne and good morning, everyone. We're happy to provide an update on recent progress against our core priorities for this year and a few forward toward key upcoming catalysts.

John M. Leonard: We're happy to provide an update on recent progress against our core priorities for this year and a view forward to our key upcoming catalyst. And in Telia, we're committed to developing curative genome editing treatments to transform the lives of individuals with severe disease, and we're proud to be at the forefront of genomic medicine, are deep scientific, technical, and clinical development expertise, and robust intellectual property portfolio, position us to transform the broad therapeutic potential of CRISPR-9 into new classes of revolutionary, Our leading platform supports a full-spectrum strategy which deploys differentiated, modular solutions across InVivo and Exvival Therapeutic Applications.

And in Chile, we're committed to developing curative genome editing treatments to transform the lives of individuals with severe diseases and we're proud to be at the forefront of genomic medicine or deep scientific technical and clinical development expertise and robust intellectual property portfolio position.

Position us to transform the broad therapeutic potential of CRISPR cash nine into new classes of revolutionary medicines.

Our leading platform supports a full spectrum strategy, which deploys differentiated modular solutions across from vivo index futile therapeutic applications for.

Genetic disease, we utilize on people approach leveraging a lipid nanoparticle based delivery system to selectively knockout disease, causing genes.

John M. Leonard: For genetic disease, we utilize our in vivo approach, leveraging a lipid nanoparticle-based delivery system to selectively knock out disease-causing genes or precisely insert genes to produce normal protein. RXVivo T-R-R-R-receptor or TCR-Base, or TCR-Base to, is designed to produce a homogeneous, robust cell product that epitomizes a patient's own Across these efforts, we have generated a broad pipeline, including emerging clinical candidates in an expansive research stage portfolio following a rapid and reproducible development path. The first quarter was a productive one for Intellia as we continued to make headway on these efforts.

Nicely and searches to produce normal proteins.

Our ex vivo T cell receptor or TCR based approach is designed to produce a homogeneous robust sell product that epitomize as a patient's own natural immune system to eliminate cancer cells across these efforts, we've generated broad pipeline, including emerging clinical candidates and an expansive research stage portfolio.

Following the rapid and reproducible development path.

First quarter was a productive one for <unk> as we continued to make headway across these efforts.

We're pleased to received the European Union's orphan drug designation for <unk> 20 on one demonstrating regulators' appreciation of the potential significant benefit eventually 20 O. One on the treatment of <unk> patients for whom there is no cure.

John M. Leonard: We were pleased to receive the European Union's orphan drug designation for NTLA 2001, demonstrating regulators' appreciation of the potential significant benefit of NTLA 201 and the treatment of ATTR patients for whom there is no cure. Additionally, we presented key preclinical data expanding our modular capabilities in new directions. In March, we introduced our proprietary base editing technology for enhanced cell engineering. In a separate presentation, we showed proof of concept for systemic invivo editing in Bellamer.

Additionally, we presented key preclinical data expanding our modular capabilities new directions in March we introduced our proprietary base editing technology for enhanced cell engineering.

A separate presentation, we showed proof of concept for systemic in vivo editing embalmed barrel per.

John M. Leonard: Platform innovations such as these lay an important foundation for Intelia's continued pipeline growth and the advancement of the next wave of genomic medicine. Finally, we were pleased to welcome Dr. Georgia Cresti, who joins our board with more than 35 years of pharmaceutical industry experience, including as a scientific and operational leader across stages of clinical development and commercial manufacturing. Our progress on these first quarter and upcoming milestones provides us with the opportunity to advance not only our core priorities for 2021 but our long-term vision for Intel.

That form innovation such as these lay an important foundation for until he has continued pipeline growth and the advancement of the next wave of genomic medicines.

Finally, we were pleased to welcome Dr. Georgia, Christie, who joins our board with more than 35 years of pharmaceutical industry experience, including as a scientific and operational leader across stages of clinical development and commercial manufacturing.

Our progress on these first quarter and upcoming milestones provides us the opportunity to advance not on their core priorities for 2021, but our long term vision for until it. We continue the evaluation of the clinical profile of <unk> 20 on one both as a potentially curative treatment option for <unk> patients.

John M. Leonard: We continued the evaluation of the clinical profile of NTLA 201, both as a potentially curative treatment option for ATTR patients and as validation of our non-viral in vivo delivery platform. In the middle of this year, we anticipate reporting our first clinical data with an interim look at our phase one study of NTLA 2001, the first systemically delivered CRISPR-based therapy, dost, and patient. In addition, we plan to submit two first-human regulatory files to advance her lead engineered TCR T cell therapy, NTLA 501 for AML, and our second Ineval Knockout candidate, NTLA 2002 for HAU. And we remain on track to nominate at least one new development candidate from our research efforts by the end of the year, with key catalysts emerging from a strong financial foundation.

And as validation of our non viral in vivo delivery platform.

In the middle of this year, we anticipate reporting our first clinical data with an interim look at our phase one study of NPL like 'twenty, one first systemically delivered CRISPR based therapy dosed in patients.

In addition, we plan to submit to first in human regulatory filings to advance our lead engineered TCR T cell therapy until a 50 or one for AML and our second in vivo knockout candidate until late 'twenty two for HCA and we remain on track to nominate at least one new development candidates from our research.

<unk> by the end of the year.

Yeah.

With key catalysts upcoming in a strong financial foundation, we are positioned to invest the resources and energy necessary to advance our pipeline expand our platform capabilities and deliver on our mission for patients with.

John M. Leonard: We are positioned to invest the resources and energy necessary to advance our pipeline, expand our platform capabilities, and deliver on our mission for patients. With that introduction, I'll hand the call over to our chief medical officer, David Leibwall, who will provide an update on our progress in a clinic with NTLA 201.

With that introduction I'll hand, the call over to our Chief Medical Officer, David Lebel, who will provide an update on our progress in the clinic with MTO late 'twenty on one day.

David.

Thanks, John and good morning, everyone.

David Neil Lebowitz: Thanks, John, and good morning, everyone. I'll start with a bit of background on ATTR and on MTLA 20. Transyretan amythus or ATPR is a rare, progressive, and fatal disease caused by the buildup of TTR protein in multiple organs. People living with the disease can have either the hereditary or wild type form of ATPR, which results in a diverse range of disease manifestations, the most frequent being polyneopathy and cardiomyopathy. Globally, there are an estimated 50,000 people with hereditary ATP and between 200 and 500,000 and 500,000 with wild type ATPR.

I'll start with a bit of background on GTR and on <unk>.

N T L. A 20 year one.

Gran <unk> amyloidosis, or <unk> is a rare progressive fatal disease caused.

On slide the buildup on GTR protein in multiple Oregon.

People living with the disease can have either hereditary or wild type form of ATT, our which results in a diverse range of disease manifestations and most frequent the polyneuropathy and cardiomyopathy.

Globally or an estimated 50000 people with hereditary ATR and between 200000 and 500000 with Wild type <unk> T. P. R.

I'm, telling you it's candidate 20th one.

David Neil Lebowitz: Intelli, 2011, applies our in-vivo lipid nanoparticle delivery technology to knock out the TTR gene in the liver, which is the source of circulating wild type and mutant TTR protein, therefore reducing amy deposition. Based on our robust preclinical data, which shows long-lasting TTR reduction of greater than 95% in non-human primates after a single dose, we believe 20-20 offers the possibility of treating and reversing In March, the European Commission granted orphan drug designation to 201.

Our in vivo lipid nanoparticle delivery technology to knock out the TCR gene in the liver.

The source of circulating wild type and mutant <unk> protein.

Therefore, reducing amyloid deposition.

Based on our robust preclinical data, which showed long lasting GTR reduction of greater than 95% in non human primates. After a single dose.

We believe 21 offers the possibility of smelting and reversing all forms of the disease with potent lifelong reduction from CRM GTR following a single dose.

In March the European Commission granted orphan drug designation to 'twenty on one.

As a reminder, this designation provides regulatory financial and commercial incentives to develop therapies for rare diseases defined as having a prevalence of less than five and 10000 people.

On the European Union.

This is meaningful as it not only reflects 20 ones potential to deliver significant benefit over existing treatments for H T. T R.

But also the unmet need remaining in this population.

David Neil Lebowitz: As a reminder, this designation provides regulatory, financial, and commercial incentives to develop therapies for rare diseases defined as having a prevalence of less than 5 and 10,000 people in the European Union. This is meaningful as it not only reflects 201's potential to deliver significant benefits over existing treatments for ATP but also the unmet need remains in this population. This is an important acknowledgement that regulators recognize the benefits of a potential single-dose treatment in indications like ATPR, even when chronic therapies exist in the market. Importantly, this is in line with our conviction in this program, as well as feedback from leading investigators who are enthusiastic about the value 201 would offer patients and our health care systems.

We view this as an important acknowledgment that regulators recognize the benefits of a potential single dose treatment in indication like a T T R.

Even when chronic therapies exist in the market.

Importantly, this is in line with our conviction on this program as well as feedback from leading investigators who are enthusiastic about the value 20th one would offer patients and our health care system.

As you May recall, our first in human trial is an open label Multicenter two part study evaluating 20 year one in adults with the hereditary form of H T T R and peripheral nerve damage.

The study will enroll up to 38 patients and consist of a single ascending dose phase in part one.

Following the identification of an optimal dose on <unk>.

Single dose expansion cohort in part two.

The trial's primary objectives are to assess the safety.

Our ability pharmacokinetics and pharmacodynamics of 'twenty, one which will include the measurement of fear on GTR levels. Following a single intravenous infusion.

The secondary objectives are to evaluate the efficacy of <unk> 21 on clinical measure of neurologic function in H GTR pn patients.

David Neil Lebowitz: As you may recall, our first in human trial is an open label, multi-center, two-part study, evaluating 201 in adults with a hereditary form of ATP and peripheral nerve damage. The study will enroll up to 38 patients and consist of a single ascending dose phase in part one, and following the identification of an optimal dose, a single dose expansion cohort in Part 2. The trial's primary objectives are to assess the safety, colorability, pharmacokinetics, and pharmacodynamics of 2001, which include the measurement of theorem TTR levels following a single intravenous infusion. The secondary objectives are to evaluate the efficacy of 201 on clinical measures of neurologic function in HTTTN patients.

Once we have established the safety and the optimal dose our goal is to expand on this study and rapidly move to pivotal studies in which we aim to enroll both polyneuropathy and cardiomyopathy patients.

By way of a clinical update we continue to enroll patients across global site and expect to share interim results from the ongoing single ascending dose portion of this study at a scientific or medical meeting in mid 2021.

These results will offer a preliminary review of the safety and activity profile of 'twenty one.

As we progress towards identifying the optimal biological dose.

We believe our interim results will establish clinical proof of concept for our modular LNP delivery platform.

An important milestone for <unk>, while demonstrating to the field at large the potential for systemic in vivo genome editing in treating life threatening diseases.

We are excited to learn how our ability to edit in vivo translates from our observations pre clinically into human.

And look forward to sharing interim results mid this year.

And with that I'll turn this over to our Chief Scientific Officer, Laura Sepp, Florida Zeno for updates on our two additional development candidates <unk> and <unk> and across our R&D effort.

Laura Sepp: Once we have established safety and the optimal dose, our goal is to expand the study and rapidly move to pivotal studies in which we aim to enroll both polyneopathy and cardiomyopathy patients. By way of clinical update, we continue to enroll patients across global sites and expect to share interim results from the ongoing single ascending dose portion of this study at a scientific or medical meeting in mid-2020. These results will offer a preliminary view of the safety and activity profile of 2001 as we progress towards identifying the optimal biological dose.

Thanks, David I'll begin with our second we believe on they'll cut from delayed MPLA tonio too in development for the treatment of hereditary angioedema R. A T E.

Hey, Jay patients experience recurring and predictable and painful attacks from swimming across multiple patients.

They are approved acute and prophylactic therapies for the treatment burden on patients remain significant.

We believe today said they should an opportunity for a therapy that not only further reduces frequency and intensity of her box, but which may prevent on medium and we need them all together.

Laura Sepp: We believe our interim results establish clinical proof of concepts for our modular LNP delivery platform, an important milestone for Intelia, while demonstrating to the field at large the potential for systemic in vivo genome editing in treating life-threatening diseases. We're excited to learn how our ability to edit in vivo translates from our observations preclinically into humans, and look forward to sharing interim results mid this year. And with that, I'll turn this over to our chief scientific officer, Lara Seploranzino, for updates on our two additional development candidates, 2002 and 501, and across our R&D F10.

Cause that and we're up line, our modular LNP delivery system for NDA late 'twenty or two to knock out the candle KD one gene in the.

The liver to permanently reduce plasma Cali crime kratky on activity.

This approach is expected to provide continuous operations of kind of current activity and eliminate the significant treatment burdens associated with currently available therapies for HIV patients.

In March we presented preclinical results at the American Academy of allergy asthma, and allergy annual meeting demonstrating NPL, a tweener to achieve greater reductions in serum <unk> protein levels on activity as compared to published results of the current standard of care for them.

These sweet actions or up to approximately 90% were sustained for Robert Blum on Halloween is single dose.

Laura Sepp: Thanks, David. I'll begin with our second in-vivo knockout candidate, NTLA 2002, in development for the treatment of hereditary Androidema or HAA. HAA patients experience recurring, unpredictable, and painful attacks of swelling across multiple tissues. Whereas they are approved acute and prophylactic therapies for HEE, the treatment burden on patients remains significant. We believe there is an additional opportunity for a therapy that not only further reduces the frequency and intensity of attacks but which may prevent and eliminate them altogether.

Boeing Nonhuman Primate study, Ohio, we're seeing a specific MMP formulation.

So on here too.

In addition, we presented data from the Humanized scale gave me one mouse model really kind of alleviated vascular permeability establishes that the single administration and the late 20th to prevent it kept a bread basket on linkage and therefore, it is expected to prevent attacks.

We continued to make steady progress with the Navy and activities and we expect to submit an IND or equivalent application for MPL eight one year or two in the second half of year.

We're leveraging insights from 10 day late 'twenty one.

And therefore anticipate being able to start from day late 'twenty or two at a higher dose for our first human study.

Which will evaluate safety tolerability and matrix of activity.

Levels of <unk> knockdown.

I will now turn to our ex vivo efforts.

Here, we're using CRISPR Cas nine as a tool to create engineered cell therapies.

Laura Sepp: To that end, we're applying our modular LNP delivery system to NTLA 2002 to knockout the KLKB1 gene in the liver to permanently reduce plasma calicrine protein and activity. This approach is expected to provide continuous suppression of calicine activity and eliminate the significant burden associated with currently available therapies for HEE patients. In March, we presented preclinical results at the American Academy of Allergy, Asthma, and Immunology Annual Meeting, demonstrating NTLA 202 achieves greater reductions in serum calicrine protein levels and activity as compared to published results of the current standard of care for EGE.

Similar to our efforts in people our proprietary approach to cell engineering on the appeals and modular platform with particularly due to mix and match cell type targeting modality and I mean, they could do interviews and it's necessary for eliciting pharmacology.

Regardless of submission, we're achieving highly efficient sequential growth with high yield.

Optimal performance and scalable manufacturing.

Our lead program <unk>, one you said potentially best in class engineered T cell therapy designed to treat all genetic subtype of AML.

[laughter] investigational candidate Ethan I would call Nicholas T cell receptor on TCR T cell therapy targeting the wilms tumor one antigen.

And then a 51 utilizes our proprietary engineering process, which is able to precisely edit and replace patients T cell receptor with a tumor targeting from CR.

These proceeds were used to safety risks and should translate to improved potency and function versus other technologies for multiplex editing.

Despite recent therapeutic advances delivering improved response rates in subsets of say you know long term outcomes continue to be core with overall five year survival below 70%.

Laura Sepp: These reductions of up to approximately 90% were sustained for over 17 months following a single dose in an ongoing non-human primate study of our synospecific LMP formulation for NTLA-202. In addition, we presented data from a humanized KLKB1 mouse model of radikinin-mediated vascular permeability, establishing that a single administration of NTLA-1U2 prevented cap-brile-induced vascular leakage and therefore is expected to prevent HA attack.

Let me give you one over expense in over 90% of AML patients regardless of subtype.

Between our proprietary sending Janine process.

On the prevalence of restarted yet we believe MPLA 51 will be a well tolerated solution capable of improving long term outcomes for patients across all mutational subtype unharmed.

We remain on track to submit an IND or equivalent regulatory application for MTL AC tier one nuclear.

Our first in human trial with day, one when the safety on a D V D. MTL, a 50 or one in patients with persistent or recurrent AML, who have previously received first linked book.

Laura Sepp: We continue to make steady progress with IND enabling activities, and we expect to submit an I&D or equivalent application for NTLA 2002 in the second half of this year. We're leveraging insights from NTLA 201 and therefore anticipate being able to start NTLA 22 at the higher dose for our first in human study, which will evaluate safety, tolerability, and measures of activity, including levels of CaliCRI knockdown. I will now turn to our ex-vibo effort.

Moving on now to our research programs and platform at that expense, we continue to make strides in developing new communities are genetic diseases and next generation engineered cell therapies for cancer.

The versatility of our approach allows us to move quickly with pipeline expansion and we remain on track to nominate at least one easy for them and can they be here.

Yeah on the first quarter, we had oral dosing patients at two of these on scientists at conferences broaden the applications of our modular toolbox.

In March we presented preclinical data at introducing our proprietary type of thing beyond me Nathan base anything technology a day.

Cold Spring Harbor laboratory and difficulty on nucleic acid therapies.

Did they buy highlight our expenses selling generic capabilities that enable us to introduce multiple on it.

On the air CRISPR as required by next generation allogeneic cell therapy.

Additionally, at the recent Keystone genome editing meeting, we presented preclinical data extending the modularity on how it may be able to leave a strategy.

Laura Sepp: Here, we're using Transburg as a tool to create engineers of therapy. Similar to our efforts in vivo, our proprietary approach to cell engineering underpins a modular platform with versatility to mix and match cell type, targeting modality, and ability to introduce the edits necessary for eliciting the desired pharmacology. Regardless of the solution, we're achieving highly efficient sequential editing with high yield, optimal performance, and scalable manufacturing.

Through our extensive M E discovery and development efforts, we identified from classic human beings that achieve those have been then could that be meaningful evidence of.

Bone marrow stem cells in a preclinical mouse model last day, one year following a single dose.

Or inherited blood disorders, such as sickle cell disease. These approach could greatly reduced the barriers to treatment associated with bone marrow transplantation.

More broadly these results demonstrate the ability to deliver to and Eddie tissues outside the liver.

We'll continue to expand up on this one with financial support provided by the bill on releasing that.

<unk> Foundation.

Although still in the research stage the technology share in these presentations on important demonstrations of our emerging capabilities.

Which together reflect our commitment to drive our pipeline cohort two continued platform innovation to create potentially curative therapies for patients.

Laura Sepp: Our lead program, NTLA 501, is a potential best-in-class engineer Kisotherapy designed to treat all genetic subtypes of AML. This investigational candidate is an autologous diesel receptors or TCR diesel therapy targeting the Wilm's tumor 1 and NTLA 501 utilizes our proprietary cell engineering process, which is able to precisely edit and replace patients' T cell receptors with a tumor targeting ECR. This process reduces safety risks and should translate to improved potency and function compared to other technologies for multiplex editing. However, despite recent therapeutic advances delivering improved response rates in subsets of A&L, long-term outcomes continue to be poor, with overall five-year survival below 30%. W1 is overexpressed in over 90% of AML patients regardless of subtypes.

Looking ahead, we plan to share preclinical data at the TCT annual meeting taking place next week.

This will include an update on our research in Alpha one Antitrypsin deficiency, which is the second disease indication for which we have demonstrated robust proof of concept for our targeted Uzi, you've always heard from technology to restart normal levels of protein in onto on Brian.

Part of it we will be sharing data on our industrial nitrogen platform utilize to derisk on I don't see heightened guys overnight that they're both both of them on heightened specifics with notice next couple off target.

These foundational work has provided us on regulators with key insights on the confidence to move our programs, including MTN late 'twenty, one forward into human clinical trials.

We look forward to these presentations next week at Inc. JCB.

With that I would like to hand over the call to our CFO, Glenn Goldberg, who will provide an overview of our first quarter financial results.

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

Our cash cash equivalents in marketable securities for a $600.8 million as of March 31, 2021, compared to $597 4 million.

Laura Sepp: And so, between our proprietary cell engineering process and the prevalence of this target, we believe NTLA 501 will be a well-tolerated solution capable of improving long-term outcomes for patients across all mutational subtypes and forms of AML. We remain on track to submit an IND or equivalent regulatory application for NTLA 51 mid-year. Our first in-human trial will evaluate the safety and activity of NTLA 501 in patients with persistent or recurrent AML who have previously received first light set.

As of December 31, 2020.

The increase was mainly driven by a $45 $3 million on proceeds from the company's at the market agreement.

$13.3 million and proceeds from employee based stock plans and $2.4 million from the Regeneron collaboration.

These increases were offset in part by cash used to fund operations of approximately $57 6 million.

Our collaboration revenue decreased by $6 5 million to $6 $4 million during the first quarter of 2021.

<unk> to $12 $9 million during the first quarter of 2020.

The decrease was driven by a $5 million milestone payment earned from Novartis for the IND submission of PQ.

P Q and 923 and 2020.

R&D expenses increased by $4 6 million to $39 $3 million during the first quarter of 2021.

Laura Sepp: Moving on now to our research programs and platform advancements, we continue to make strides in developing new therapeutic candidates for genetic diseases and next generation engineers of therapies for cancer. The versatility of our approach allows us to move quickly with pipeline expansion, and we remain on track to nominate at least one new development candidate this year.

<unk> to $34 $7 million during the first quarter of 2020.

This increase was mainly driven by the advancement of our lead programs.

Research personnel to support these programs and the expansion of our development organization.

G&A expenses increased by $2 3 million to $13 $6 million during the first quarter of 2021.

Compared to $11 $3 million during the first quarter of 2020.

This increase was related to employee related expenses, including stock based compensation.

$9 million.

Laura Sepp: During the first quarter, we had oral presentations at two different scientific conferences, broadening the applications of our modular tool. In March, we presented preclinical data introducing our proprietary cytosine deaminase base editing technology at the Cold Spring Harbor Laboratory Scientific Meeting on Nuclear Therapy. The data highlights our expansive cell engineering capabilities that enable us to introduce multiple edits via CRISPR as required by next-generation allogenic cell therapy. Additionally, at the recent Keystone Genome editing meeting, we presented preclinical data extending the modularity of our in-divow delivery strategy.

Finally, we expect our current cash balance to fund operating plans through at least the next 24 months.

And now I will turn the call back over to John for closing remarks.

Thank you Glenn.

As you can see there are many reasons for excitement for what the remainder of the year holds for our company and the field of genomic medicines.

Our phase one study of until late 'twenty on one is progressing well and we look forward to sharing interim results mid this year for clinical validation of our platform.

We continued to progress our pipeline and expect to file a first in human regulatory submission midyear from T. L. A 50 or one.

In addition, we expect to submit an IND or IND equivalent application for until late 'twenty or two from this.

Second half of this year.

We are advancing on research stage portfolio as we expect to nominate at least one new development candidates a share and we continue to expand our toolbox to enable the next wave of genomic medicines.

Laura Sepp: Through our extensive MNP discovery and development efforts, we identified a class of MNPs that achieve this dependent, therapeutically meaningful editing of bone marrow and hematopoietic stem cells in a preclinical mouse model lasting one year following a single doctor. For inherited blood disorders such as sickle disease, this approach could greatly reduce the barriers to treatment associated with bone marrow transplantation.

With all this progress and as we close in on key milestones, we remain focused on our core priorities and wholly committed to making genome editing as promised a reality for patients.

Well now open the line for any questions operator.

Thank you we will now begin the question and answer session.

To ask a question you May press Star then one on your telephone keypad.

If youre using a speakerphone please pick up your handset before pressing the case.

To withdraw your question. Please press Star then two.

At this time, we'll pause momentarily to assemble our roster.

The first question today comes from Celgene Brookdale with Goldman Sachs. Please go ahead.

Great. Thank you so much for taking our question. This is sonya on for solving they have a few questions on I'm, telling you on two O O on them. So the first is what data should we expect from the Reed and mid 'twenty one on how.

Glenn G. Goddard: More broadly, these results demonstrate the ability to deliver to and edit tissues outside the liver. We will continue to expand upon this work with financial support provided by the Bill and Melinda Gates Foundation. Although still in the research stage, the technologies discussed in this presentation are important demonstrations of our emerging capabilities, which together reflect our commitment to drive our pipeline forward through continued platform innovation to create potentially curative therapies for patients.

Many cohorts should we expect data from and then the second question is what is the status of the IMD for until two O O. One in the U S. Thank you.

So on yet.

For the question.

First of all just to remind you.

<unk> 20 on one is a study that were.

We're currently studying 21 outside the United States. So for this first in human study, there's no plan to have an M. D. As part of this particular study the expectation is that for subsequent work we would come back to the U S have an ideal day for work that would involve cardiomyopathy in subsequent studies with risk.

Back to the ongoing study and the data we anticipate presenting.

Glenn G. Goddard: Looking ahead, we plan to share preclinical data at the ASGCT annual meeting taking place next week. This will include an update on our research in Alpha-1 Antitrips in deficiency, which is the second disease indication for which we have demonstrated robust proof of concept of our targeted in vivo insertion technology to restore normal levels of proteins in non-Gium primates. Further, we will be sharing data on our industrialized screening platform utilized to derisk and identify guide RNAs that are both potent and highly specific with no detectable off-target edit.

Not talking about the number of cohorts other than to say that we progressed well with the study as it was laid out.

And we're adhering to the principles that we will have substantive data that's readily interpretable and we look forward to sharing that.

Glenn G. Goddard: This foundational work has provided us and regulators with key insights and the confidence to move our program, including NTLA 201, forward into human clinical trials. We look forward to these presentations next week at ASGCT. With that, I would like to hand over the call to our CFO, Glenn Godd, who will provide an overview of our first quarter financial results.

Questions to on I E. L N P design and I get some of the characteristics that go into your to your on L. PS and I'm wondering if we could learn more about that in the mid year update and how high your L. M. P's Uhm Functionalist Asian translates to an improvement in.

Immunogenicity and also the tunable tropism as well.

Thanks is the ear unfolds I'm sure there's gonna be opportunities to talk more about the platform into work that we're doing I think with respect to the clinical data that we're talking about I would I would anticipate that most of the discussion at that time would be about the study and the results that we have but.

Glenn G. Goddard: Thank you, Laura, and good morning. Teller remains in a strong financial position as we advance our pipeline. Our cash, cash equivalents, and marketable securities were $600.8 million as of March 31, 2019, compared to $597.4 million as of December 31st, 2020. The increase was mainly driven by $45.3 million of proceeds from the companies under the market agreement, $13.3 million in proceeds from employee-based stock plans, and $2.4 million from the Regeneron Collaboration.

As you know Maury as as our science progressive there's points, some time or we'd like to share some of the advantages that we have in there maybe opportunities later this here to do that.

Makes sense, okay. Thank you for taking my questions.

Sure.

Thank you.

Your next question comes from my Jane away with that day.

Go ahead.

Hi, This is Sheldon all 14, thanks for taking on real question.

So I think you mentioned in the past that the target knocked on level about this 80 per cent for the for the old one trial. So right now you have almost set up the timing of the presentation doesn't mean, you're already reached the target level in the initial all those levels.

HM.

So the way we've approached this is we've said from the outset that we would share interim data from the study is to progress. If you remember that there's two phases towards the sending those face and on the expansion phase, where we would take what we think will be the optimal biological dose and studies have more fully in it.

Glenn G. Goddard: These increases were offset in part by cash used to fund operations of approximately $57. Our collaboration revenue decreased by $6.5 million to $6.4 million during the first quarter of 2021, compared to $12.9 million during the first quarter of 2012. The decrease was driven by the $5 million milestone payment earned from Novartis for the I&D submission of OTQ 93 in 2020. However, R&D expenses increased by $4.6 million to $39. during the first quarter of 2021, compared to $34.7 million during the first quarter of 2020.

Larger set of patients.

The principle that we've applied for this first phase of the study is that will have a meaningful results that are readily interpretable, we haven't tied that to a specific target for this particular day to release. It is true that we set as a benchmark 80 per cent and beyond.

Our objective is to surpass 80 per cent because we think the further one reduces the circling teach your levels more beneficial it's gonna be for patients and I think there's places we can look for a day does that seems to indicate that so that is our ultimate objective.

But the particular day to we share here is not necessarily triggered by any specific number.

Glenn G. Goddard: This increase was mainly driven by the advancement of our lead program and research personnel to support these programs in the expansion of our development organizations. G&A expenses increased by $2.3 million to $13. During the first quarter of 2021 compared to $11.3 million during the first quarter of 2005. This increase was related to employee-related expenses, including stock compensation of.9 million dollars.

Thank you so much.

Thank you.

Your next question comes from that money for on it.

BB Leerink. Okay go ahead.

Hi, Good morning. This is Rick on the line for money, Okay. Thanks for taking our questions.

John M. Leonard: Finally, we expect our current cash balance to fund operating plans through at least the next 24 months. Now, I will turn the call back over to John for closing remarks. Thank you, Glenn.

John M. Leonard: As you can see, there are many reasons for excitement for what the remainder of the year holds for our company and the field of genomic medicine. Our Phase 1 study of NTLA 2001 is progressing well, and we look forward to sharing interim results mid this year for clinical validation of our platform. We continue to progress our pipeline and expect to file a first in human regulatory submission mid-year for N PLA 50-O-1.

You take index that does not trigger those particular LNP class effects and.

Let's face one study is to test exactly that was preclinical findings and as we've said we'll share some of the early results here mid this year with respect to novel components.

John M. Leonard: In addition, we expect to submit an I&D or I&D equivalent application for NTA 2002 in the second half of this year. We are advancing a research stage portfolio, as we expect to nominate at least one new development candidate this year, and we continue to expand our toolbox to enable the next wave of genomic medicines. With all this progress, and as we close in on key milestones, we remain focused on our core priorities and wholly committed to making the genome editing promise a reality for patients. We'll now open the line to any questions. Operator? It is.

Just the way I think about it is the the LNP is largely precedent that yes, there is a unique piece.

Peace too it's that is the proprietary lippard had ionic Ah lipid.

Well, we think we characterize that very very well and no very well how it behaves based on on preclinical work and the rest of it is RNA, either guide or mrna and and again, we think you should really good preclinical models for that with respect to the genomic characterization of the effects that's been extensively.

The address preclinical day, I would say more than probably any other drug as far as I'm aware.

And I would encourage you to attend the S. P. C T meeting, where we're gonna go through a lot of how that work is done so you've got a really good sense of the completeness and the extent of that effort. So we can maybe revisit after we go through that data later this month.

Operator: Thank you. We will now begin the question and answer session. To ask a question, you may press star, then one on your telephone keypad. If you're using a speaker sign, please pick up your handset before pressing the case.

Got it I really appreciate all the detail there and thanks again for taking the question.

Sure.

Thank you.

Your next question comes from Jane Labor True. Please go ahead.

Hi, Thanks for taking our questions.

You know you just set your a bar is 80%, which is what I get.

I guess, that's R N as in that sense of articles have around that knocked.

Operator: To withdraw your questions, please press start, then to. At this time, we'll pause momentarily to assemble our roster. Your first question today comes from Selvine Ristel with Goldman Sachs. Please go ahead. Hi, thank you so much for taking our question. This is Sonia on behalf of Selveen.

Knocked out level, but then you know as a genome editing so that is constantly working day evening need to hit similar knockdown as as those you know.

And you said solid colors or authority, chief similar kind of classy or could you envision a situation, where you could get less knocked on by still get equivalent or better clinical effect and could we get clinical data midyear as well as somehow knock on levels and I have a follow up on us.

So it's a very important question on your asking which is when we talk about these numbers and knocked on what does it actually mean right and so the numbers are typically presented by somebody other modalities that I'm familiar with at least for.

Sonia: We have a few questions on Antelia 201. So the first is, what data should we expect from the read in mid-21? How many cohorts should we expect data from? And then the second question is, what is the status of the I&D for Intellia 201?

Are typically portrayed as maximum effects.

And what what you're asking is essentially an area under the curve question, which is well [noise] [noise].

Excuse me if you have a maximum effect on a particular number call at 80 per cent what is the average effect over time.

And one of the advantages of the approach that we're taking here is that the maximum effect is the effect because there's no pharmacokinetic of variability that occurs over time.

John M. Leonard: for Intelia 201 in the U. Thank you. Sonia, thanks for the question.

John M. Leonard: Sonia, uh, thanks for the question. First of all, just to remind you, 201 is a study that we're currently studying 201 outside the United States. So for this first in human study, there's no plan to have an I&D as part of this particular study. The expectation is that for subsequent work, we would come back to the U.S. and have an I&B for work that would involve cardiomyopathy and subsequent studies. With respect to the ongoing study and the data we anticipate presenting, we're not talking about the number of cohorts other than to say that we have progressed well with the study as it was laid out, and we're adhering to the principles that will have substantive data that's readily interpretable, and we look forward to sharing.

So.

You know our our approach to this is we look at 80 per cent as the benchmark. The goal is to surpass it not just from a maximum effect, but from a sustained effect in a few go back to some of the preclinical data that we presented you'll see that when it comes to the animal models, that's exactly what we achieved so our thesis.

Is that [noise], reducing T T R. Two the lowest possible levels in the blood is going to lead to a more clinical benefit and that's exactly what we're setting out to achieve here. So that's how we think about it.

Oh, Okay, So I'm gonna get clinical day, along with him knock down here.

So in in the early phase of the study remember, it's a three plus three designers for cohorts. So the extent of clinical data I think it's gonna be very modest here early on I would I would look too is primarily a safety characterization and primarily a T. T R effect.

There is descriptive clinical data, but the bulk of that information I would look to the second phase of the study.

Got it and then one more question yeah for the people keen on editing force I'm Gonna put it some sales what is the distribution of bone marrow trophic L. M P and deliver versus bone marrow and how 'bout that plane to be overall efficacy and your ability of disappeared for sickle cell disease and he does this program taken.

Maurice Thomas Raycroft: Your next question comes from Maury Rafe with Jeffrey.

David Neil Lebowitz: Hi, good morning, and congrats on the progress. I just had a question about the 201 clinical study. Just wondering if there's anything additional you can say on safety so far in the clinical study. I guess one concern in the past has been immunogenicity, and is there anything you can say about that at this point, and will that be part of the mid-year update? Thanks, with respect to safety, I think it's best to look forward to the information that we anticipate sharing here mid-year. The study is progressing, and we're excited about the progress that we've made, and, you know, I think we'll address many of your questions at that point in time.

Take any priority and the overall per forgive strategy, giving me announcement between Chris.

Crisper and of our techs or they seem to be moving aggressively to to commercialize this or does not impact your overall strategy or or do you have something in agreement with novartis that that kind of limits your ability to to develop.

Their critics force.

Thank you that's a big question with many sub parts I I'll tell you, how we think about it.

David Neil Lebowitz: And then we've been getting questions too on LNP design and I guess some of the characteristics that go into your LMPs, and I'm wondering if we could learn more about that and the mid-year update and how your LMPs functionalization translates to an improvement in immunogenicity and also the tunable tropism as well.

John M. Leonard: Thanks. As the year unfolds, I'm sure there'll be opportunities to talk more about the platform and the work that we're doing. I think with respect to the clinical data that we're talking about, I would anticipate that most of the discussion at that time would be about the study and the results that we have. But as you know, Maury, as our science progresses, there are points in time where we like to share some of the advantages that we have, and there may be opportunities later this year to do that. Makes sense. Okay, thank you for taking my questions. Sure.

Gena Wang: Your next question comes from Gina Wang, with Bye, please. Please go ahead.

Sheldon: Hi, this is Sheldon, now for Gina. Thanks for taking out the requests. So I think you mentioned in the past that the target knockdown level is about 80% for the 2001 trial. So right now, you have almost set up the timing of the presentation. Does that mean you have already reached the target level in the initial stages of those levels? the way we've approached

Sales of transplant, we know how to edit it's just getting rid of the bone marrow transplantation. So our belief is that solving that with an in vivo in vivo delivery system that is what will address the fundamental problem here. So other relationships and other approaches that people take we admire their work and encourage them to proceed.

John M. Leonard: The way we've approached this is we said from the outset that we would share interim data from the studies of progressives. Remember that there are two phases to it, the ascending dose phase and then the expansion phase, where we would take what we think will be the optimal biological dose and study that more fully in a larger set of patients. The principle that we've applied for this first phase of the study is that we will have meaningful results that are readily interpretable.

Our approach is to have something that we think will have the broadest reach and the best solution for the greatest number of patients and that is.

What we're working on and that's what the Gates Foundation has been helping us to do.

Thank you and looking forward to data.

Thank you.

Thank you.

Your next question comes from Steven Greathouse with Raymond James.

Please go ahead.

Thank you and good morning, I'm surprised to see your guiding to submitting an I N D. R. I N D equivalent with your follow on products. It just seems to imply that either you havent decide.

John M. Leonard: We haven't tied that to a specific target for this particular data release, but it's true that we set as a benchmark 80% and beyond. Our objective is to surpass 80% because we think the further one reduces the circulating TTR levels, the more beneficial that's going to be for patients. And I think there are places we can look for data that seems to indicate that. So that is our ultimate objective, but the particular data that we share here is not necessarily triggered by any specific data.

Decided which geography you plan to proceed or that you don't want to say on it I guess I just don't understand why the ambiguity are intriguing is even necessary.

Yes.

You really don't know and kind of ex U S trial as a backup plan at this point that's basically how it reads to me. So my question is I was just hoping you could be clear do you actually have plans to file.

While U S. I N D near term for H a R. M. L. A or can you say already right now those will be ex U S trials and if you arent certain about our U S. A N D. Still can you say have you had any pre IND meetings recently and can you share insights from those interactions. Thank you.

Well, we're not going to change what we've said, but I. Thank you for the question will be in a position to give you more clarity as we proceed here we share exactly the same guidance with respect to until a 20 O on.

John M. Leonard: The next question comes from Mani Bora with SVB Lyrink.

Mani Foroohar: Hi, good morning. This is Rick on the line for Moni. Thanks for taking our questions. So I actually have a follow-up question on safety and specifically

We are very very engaged on the regulatory interactions and we certainly are and discussing things with the FDA as well as other regulators and we're putting yourselves in a position where we can have the broadest base program that gets the most clinical information most efficiently so.

Rick: There are a few novel components being evaluated here.

Rick: for the first time in the clinic, and you know, that's the LNP.

Rick: LMP formulation, the transient expression of cast 9 and guide RNA in the liver, and then the actual edits being made to the genome.

I'm I'm, sorry, I'm not going to be able to address specifically on your question, but as time unfolds here. It will we'll share more information.

Rick: So I was hoping to just get your thoughts on if there are any.

Rick: Is any sort of safety signal observed in the trial, and what ability is there to

I appreciate it thank you.

Thank you.

Your next question comes from Ian Ing with Wells Fargo Securities.

Please go ahead.

Rick: parse out which sort of those components may be contributing to the signal and, you know, potential

Hi, Thanks for taking my questions on.

A few questions on it 2000 Y on it first in terms of the place the venue.

John M. Leonard: and, you know, potential read-throughs for the rest of the InVo platform. Yeah, so we're talking in general about safety, and the way we approach it is, you know, there's the LNP itself and its administration, and then there's the long-term effects of that particular intervention, which we expect to be largely beneficial based on the expected TTR knockdowns that we've achieved in animals. LMPs as a class, you may remember Rick, generally have a characteristic pattern of safety findings that when one gives sufficient quantities of material, you can trigger.

On the medical on me.

The specific medical meeting we are is it reasonable to assume that it is a P. N S meeting in June.

And also could you characterize I don't know more what you mean by interpret bar interpretable data on does that mean a day it had a within a certain variability that you could.

And make a judgment of the result or doesn't mean at your ability to project some kind of a dose response to predict what might happen with additional dosing.

Any color on that will be very helpful.

Thank you.

Sure. Thank you with respect to the particular, meaning we're not sharing that information just yet however, [noise].

We won't be surprising people as we get closer to that point in time, we will share in a press release, when and where so people I think we will have plenty of information in advance to be prepared to attend the meeting or interact with it.

John M. Leonard: All that we've worked on very, very carefully in our preclinical work to develop a therapeutic index. So the clinical exposures that we're doing in the human trial here are designed to balance the desired and expected TTR effects within the therapeutic index that does not trigger those particular LNP classes. And, you know, the space one study is to test exactly those preclinical findings. And as we've said, we'll share some of the early results here mid this year.

To get the information with respect to interpretable data, that's a principle that we've applied which really speaks to exactly what you said with small numbers of patients are in and an ascending dose study when I always pays attention to.

Variability if it's there.

And one wants to be able to look at those data. She if theres an effect and help make some assessment of what it's likely to mean for not only <unk>.

John M. Leonard: With respect to novel components, you know, I guess the way I think about it is that the LMP is largely precedented. Yes, there is a unique piece to it that is the proprietary lipid or cationic lipid. But we think we characterize that very, very well and know very well how it behaves based on preclinical work. And the rest of it is RNA, either guide or MRNN, and again, we think there are really good preclinical models. With respect to the genomic characterization of the effects, that's been extensively addressed preclinically, I would say more than with probably any other drug, as far as I'm aware.

Until late 'twenty one.

And how it will fit into the Pharmacopeia, but also on our platform generally and so those are the principles that we apply then I think when we're on a position to assure the data you'll see that we've addressed them.

Thank you a quick follow up.

Your EU orphan drug designation application.

The committee I ask for a clinical data.

I think because you know obviously there are a chronic therapies.

You know some precedents when multiple when there is a standard of care the committee might ask for data when determining the orphan drug status. Thank you.

Yeah, I think the committee is it makes us determination asks whether or not there's remaining unmet need.

John M. Leonard: And I would encourage you to attend the ASPCPC meeting where we're going to go through a lot of how that work is done so you get a really good sense of the completeness and the extent of that effort. And we can maybe revisit it after we go through that data later.

And they concur with the broad based a source of information.

The weekend, which includes kols patients and treating health care personnel. So it's it's less about a clinical information it's about the status of the current treatment state of the art.

Rick: Got it. I really appreciate all the detail there, and thanks again for taking the time to ask the question.

Joon So Lee: Your next question comes from June Lee with Truitt. Please go ahead.

Got it thank you.

Joon So Lee: All right, thanks for taking our questions.

Mhm.

Thank you.

Your next question comes from at Sylvan per Ken with JMP Securities Inc.

John M. Leonard: you know, you just set your bar as 80%, which is what, I guess, SRNAs and anti-s, all that goes, hover around that knockdown level. But, you know, as a genome editing tool that is constantly, you know, working, do you really need to hit similar knockdown as those and desensitize solidly both SR&A to achieve similar clinical efficacy, or could you envision a situation where you could get less knockdown but still get equivalent or better clinical effects?

Go ahead.

Thank you congrats on all the progress on thank you for taking my question.

First off I wanted to ask about a comment from Iraq.

Could I just please confirm that you mentioned that you may want to start and tell you 22 at a higher dose comparison on Italian out 'twenty one.

And if that is the case can we read across from that information to entire 20 O on saying that.

The slowest growth, there's probably pay for it but it may have been too Hello. Thank you and then I have a follow up.

I'll I'll stay on and floor out here I guess I'm just to keep it efficient, but you know it.

John M. Leonard: And could we get clinical data mid-year as well as some knockdown levels, and I have a follow-up. So it's a very important question you're asking, which is when we talk about these numbers of knockdown, what does it actually mean, right?

It all goes back to the fundamental premise of modularity.

So whether it's on the research side, whether it's on the preclinical side or on on the political side, what we learn for an L. N P and its cargo broadly of parts and so as we collect information from any of those different domains are what we've found is that we can.

John M. Leonard: And so the numbers are typically presented by some of the other modalities that I'm familiar with, at least, are typically portrayed as maximal effects, and what you're asking is essentially an area under the curve question, which is, well, excuse me, if you have a maximal effect at a particular number, let's call it 80, what is the average effect? And one of the advantages of the approach that we're taking here is that the maximal effect is the effect because there's no pharmacokinetic variability that occurs over time.

Apply it to subsequent incarnations of the product in various.

He's our regulatory interactions or even clinical interactions so.

The information that we have.

I'm not going to characterize it other than that it's able to give us some bearing on how we approach our 20 O two and it.

It may have some utility there.

Thank you so much on my follow up question is.

What you have read possible re dosing in the expansion part of the Ah Ah trial for patients that don't reach the target knockdown levels are for some reason or is that something you would explore in a in a later trial.

John M. Leonard: You know, our approach to this is we look at 80% as the benchmark, and the goal is to surpass it, not just from a maximal effect but from a sustained effect. And if you go back to some of the preclinical data that we presented, you'll see that when it comes to the animal models, that's exactly what we achieve. So our thesis is that reducing TTR to the lowest possible levels in the blood is going to lead to more clinical benefit, and that's exactly what we're setting out to achieve here. So that's how we think about it.

Yeah broadly based in terms of how to go to trial. It's normally a single ascending dose study in a single application. There are provisions that were making in the course of the program and perhaps are in the study. This is work that we're.

Addressing where.

Suboptimal doses if they occur.

Those patients may have subsequent recourse to a more active dose, but as that gets clarified we'll be in a position to talk more about it.

John M. Leonard: Okay, so will we get clinical data along with the knockdown?

Okay.

John M. Leonard: So in the early phase of the study, remember it's a three plus three design, there are four cohorts, so the extent of clinical data, I think, is going to be very modest here early on. What I would look at is primarily a safety characterization and primarily a TTR effect. There are descriptive clinical data, but the bulk of that information I would look at in the second phase of the study. Okay.

One quick last question, that's on I talked about on Big picture.

Are there any pitfalls that you can point to if you would compare the until the 'twenty on one dataset to harmonize all politics are on in terms of a time to peak or steady state a knockdown level or a patient populations or anything you can point us to for this readout to tell us a watch out for this on.

Alright.

So I'm not sure I got the Gist of your question that you're asking about our family. This knockdown effects versus until late 'twenty. One is that what you asked me.

Joon So Lee: And then one more question. You know, in vivo genome editing for humanoid cells, what is the distribution of bone marrow-tropic L&P in the liver versus bone marrow? And how does that play into the overall efficacy and durability of this approach for sickle cell disease? And, does this program, you know, take any priority in the overall performance of your strategy given the announcement between, you know, CRISPR and Vertex, or do they seem to be moving aggressively to commercialize this, or does this not impact your overall strategy? Or do you have something in agreement with no artist that kind of limits your ability to develop their contract?

When we when we get the Oh reduction from until they're 20 on one.

What if I'm not a straightforward comparisons we can do to the other agents and what what are some of the.

On a watch out for in terms of just stable.

Markdown levels, etc.

Yeah, I mean with respect to this particular study.

There are exclusions with respect to what other people can take or will have taken ever before coming into the trial. So in terms of measuring any of that and of course of that study directly that that won't be a part of it with respect to the behavior of GTR in its decline.

I think there'll be a fair amount of information that we would expect to interpret and one can look at ESI RNA material and you know what.

It shows the relevant knockdown comparator I think P. T R P.

PTR levels are are not knocked down by <unk>. So it's a different kind of a calculus on what might make.

John M. Leonard: That's a big question with many subparts. I'll tell you how we think without going into all the specifics of, you know, distribution between liver and bone marrow and various other compartments of the body. Obviously, the objective is to get the right amount to the appropriate cells in the bone marrow. And it's very clear that LMPs, as a class, have a tendency to be picked up fairly avidly by the liver.

But you know I think one would expect to have.

On a pretty good.

You know a set of data to make some broad based comparisons based on what we're expecting to share.

So thank you for taking my question and congrats on all the progress is true.

Thank you.

Your next question comes from Jay Olson with FBR. Please go ahead.

Oh, Hey, thanks for taking the question.

For the base editor your system that you recently presented well that based editor be used in both in vivo and ex vivo programs and how do you plan to integrate that into your overall platform.

John M. Leonard: So part of the delivery challenge is addressing the avidity of that body, clearance that takes place in the liver, and we've made good head weight with respect to that. And there are a variety of ways to do that, and our scientists are working on many of them. And it's premature at this point to talk about exactly how we're doing that. But as, you know, time unfolds here, I'm sure there'll be opportunities to talk more about it.

Yeah. Thanks for the question.

We're very excited about what particular sorts of applications based centers may be applied to we see.

Their greatest utility in the ex vivo setting.

It's not currently a part of the programs we've been talking about if you saw the presentation, who gave a cold spring Harbor.

One of the things that we're very mindful of is the state of the art in terms of looking for stochastic off target effects and the in vivo setting and that's where we think there's additional work to be done from the field broadly.

John M. Leonard: Just broadly speaking about sickle cell and related disorders of the humanopoetic system, we're very excited by the progress that others have made that shows, I think, pretty clearly that one can edit hemipoleic stem cells and treat sickle cell disease pretty effectively. And that's great news for that set of patients who, we all know, have long suffered with very, very, you know, inadequate sorts of therapeutic treatment. The challenge is that to get to those benefits, one needs to be subjected to a bone marrow transplant, which brings significant morbidity and, even in some cases, mortality. And so our view is that the final endgame here is avoiding that bone marrow transplant. We know how to edit.

So in the nearest term we think that the ex vivo setting is probably the best place to use to pay et cetera, but I'm sure work will continue and that may change over time.

Yeah.

Great. Thank you and then maybe one follow on question.

Here upcoming presentation at TCT, what kind of preclinical data should we be looking for and what are the gating factors to moving that program on to the next steps.

Well, the and HTC Chi remember, there's two presentations that we're making one is a very detailed analysis of.

Is the off target approach, which speaks broadly true what we do so it doesn't relate necessarily to any particular program.

The other.

Our presentation will be on extended information on Alpha one Antitrypsin program.

We're not talking yet about its status with respect to the pipeline its candidacy et cetera, we will have a third presentation, where CSO will also be speaking broadly about the gene editing and its clinical utility so there'll be some other insights, but we won't be talking about COVID-19.

John M. Leonard: It's just getting rid of bone marrow transplantation. So our belief is that solving that with an in vivo delivery system is what will address the fundamental problem here. So other relationships and other approaches that people take; we admire their work and encourage them to proceed. Our approach is to have something that we think will have the broadest reach and the best solution for the greatest number of patients. And that is what we're working on, and that's what the Gates Foundation has been helping us to do. Thank you.

Particular development candidates and changing their status there.

Great. Thanks for taking the questions.

Sure.

Thank you.

Next question comes from Jay Allen with Baird. Please go ahead.

Hi, Thank you Shai Jack Allen here. Thanks, so much for taking the question. We wanted to touch briefly on N T. L. A 2002 and we were wondering if you could talk a bit about your expectations for the trials you're moving towards the clinic. It's our understanding that there are a number of therapies already approved for H, a how do you expect the magnitude of clinical.

Joon So Lee: Thank you. I'm looking forward to the data.

Steven James Seedhouse: Your next question comes from Steven Seedhouse with Raymond James.

Benefit here as you as you move it into the clinic and then I know someone touched on this earlier, but you briefly mentioned that you may file on India, India equivalent for this program by the end of the year could you speak to the factors that are going to dictate the decision to go with an eye on D or R&D equivalent is the N T. L. A 2000 on one data one of the factors that you're weighing in that decision.

Steven James Seedhouse: Please go ahead.

John M. Leonard: Thank you, good morning. I'm surprised to see you guide us to submitting an I&D or IND equivalent with your follow-on products. It just seems to imply that either you haven't, you know, decided which geography you plan to proceed with or that you don't want to say. And I guess I just don't understand why the ambiguity or intrigue is even necessary, unless, you know, you really don't know, and the XUS trial as a backup plan at this point. That's basically how it reads to me.

Do you so much.

Yeah.

Yes, just a couple of words about where we think until a 20 O two can fit on the pharmacopeia.

Hum.

We think that the modality that we have is ideally suited to hereditary angioedema.

It's certainly the case that advances have been made with respect to treating that condition.

These are patients are treated as an attack occurs patients don't like net where theyre prophylaxis with ongoing therapy. Remember. These are patients who are typically are identified at the time of puberty or shortly thereafter, so essentially what youre talking about is lifelong therapy.

John M. Leonard: So my question is, I was just open so you could be clear, do you actually have plans to file a U.S. I&D near term for H.A.E or AML, or can you say already right now, those will be XUS trials? And if you aren't certain about a U.S. I&D still, can you say, have you had any pre-I&D meetings recently, and can you share Thank you.

It is a very very significant treatment burden and one that I'm in.

In some cases has become a quite effective and others is far less so so therapeutic opportunity clearly remains.

Don't forget also that most effective therapies are extremely expensive starting at over half a million dollars per year with many patients spending over $1 million a year for those same therapies, so whether it's the.

John M. Leonard: Well, we're not going to change what we've said, but I thank you for the question. We'll be in a position to give you more clarity as we proceed. We share exactly the same guidance with respect to NTLA 2001. We are very, very engaged in the regulatory interactions, and we've certainly been discussing things with the FDA as well as other regulators, and you are putting yourselves in a position where we can have the broadest-based program that gets the most clinical information most efficiently. So I'm sorry I'm not going to be able to address your question specifically, but as time unfolds here, we'll share more.

Meeting and exceeding the effect that others have achieved or whether it's dealing with the burden of treatment or dealing with the significant.

Pharmacopeia economic cost to the health care system sales patients, we think that we have something to offer on every single front.

With respect to the clinical trial, and where we do it.

We certainly look across all the work that we do wherever it is and whatever the drug is in factor than how we think about what we're where we're what we're doing how we're doing it where were going to do it.

We would expect that to be a.

Very central factor in our ultimate decision on where we carry this workout.

Ian and Zoo: The next question comes from Ian and Zoo from Wells Fargo Securities.

Thank you so much.

Sure.

Thank you.

There was no time for further questions I will now hand back to line up for closing remark.

Ian and Zoo: Hi, thanks for taking my questions.

John M. Leonard: The place the venue of the medical meeting, the specific medical meeting; is it reasonable to assume it is the PNS meeting in June? And also, could you characterize a little more what you mean by interpretable data? Does that mean data within a certain variability that you could make a judgment of the result, or could it mean your ability to project some kind of dose response to predict what might happen with additional dosing? Any color around that.

Great. Thank you all for joining us today and for your continued interest and support we look forward to updating you on our progress and have a wonderful day.

Yeah.

That does conclude our conference for today. Thank you for participating you may now disconnect your line.

Okay.

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John M. Leonard: Sure, thank you. With respect to the particular meeting, we're not sharing that information just yet. However, we won't be surprising people as we get closer to that point in time; we will share in a press release when and where. So people, I think, will have plenty of information in advance to be prepared to, you know, attend the meeting or interact with it to get the information. With respect to interpretable data, that's a principle that we've applied, which really speaks to exactly what you said about small numbers of patients in an ascending dose study.

Yeah.

Okay.

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John M. Leonard: One always pays attention to variability if it's there, and one wants to be able to look at those data to see if there's an effect, and how, you know, make some assessments of what it's likely to mean for not only until 8201 and how it will fit into the pharmacopoeia but also our platform generally. And so those are the principles that we've applied, and I think when we're in a position to share the data, you'll see that we've addressed Thank you.

John M. Leonard: A quick follow-up, in your EU orphan drug designation application, did the committee ask for clinical data? I think because, you know, obviously, there are chronic therapies, and some precedents when multiple, when there is a standard of care, the committee might ask for data when orphan drops. Yeah, I think the committee, as it makes this determination, asks whether or not there's remaining unmet need, and they concur with the broad-based source of information that we get, which includes KOLs, patients, and, you know, treating health care personnel. So it's less about clinical information. It's about the status of the current treatment state of the art.

Silvan Can Tuerkcan: Your next question comes from Sylvan Kirkken with JMP Securities. Please go ahead.

Silvan Can Tuerkcan: Thank you, and congratulations on all the progress, and thank you for taking my advice.

John M. Leonard: and thank you for taking my question. First of all, I wanted to ask about a comment from Laura, and could I just please confirm that you mentioned that you may want to start Antelia 2002 at a higher dose compared to Intellia 201? And if that is the case, can we read across from that information to Intelliard 201, saying that the first slowest dose is probably safe or that it may Thank you and then have a follow-up. I'll stand in flora here, I guess, just to keep it efficient.

John M. Leonard: But, you know, it all goes back to the fundamental premise of modularity. So whether it's on the research side, whether it's on the preclinical side, or on the clinical side, what we learn about an LNP and its cargo broadly applies. And so as we collect information from any of those different domains, what we found is that we can apply it to subsequent incarnations of the product and various regulatory interactions or even clinical interactions.

John M. Leonard: So the information that we have is, I'm not going to characterize it other than that it's able to give us some bearing on how we approach 2002, and it may have some utility. Thank you so much.

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Silvan Can Tuerkcan: And my follow-up question is, Could you have possible redosing in the expansion part of the trial for patients that don't reach the target knockdown levels for some reason, or is that something you would explore in a later trial? Yeah, broadly speaking in terms of how to think about the trial, it's formerly been a single sending dose study in a single application. There are provisions that we're making in the course of the program, and perhaps in this study, this is work that we're addressing where suboptimal doses, if they occur, those patients may have subsequent recourse to a more active dose.

Silvan Can Tuerkcan: But as that gets clarified, we'll be in a position to talk more about it. Okay, thank you. And maybe one quick last question, if I may. Just on the big picture, are there any pitfalls that you can point to if we compare the Intelliator 201 data set to Tamadiz or Petisoran in terms of time to peak or study states, knockdown level, or patient populations? Anything you can point us to, for this reader, to tell us to watch out for this or just make people follow it?

John M. Leonard: So I'm not sure I got the gist of your question. You're asking about tephamidus and knockdown effects versus Nchle 21. Is that what you asked me?

Silvan Can Tuerkcan: Yeah, when we get the COD reduction from Mantella 2001, what are some of the straightforward comparisons we can do to the other agents and what are some of the things I think you have to watch out for in terms of, you know, you know, you know, knockdown levels. Yeah, I mean, with respect to this particular study, there are exclusions with respect to what other people can take or will have taken ever before coming into the trial.

Silvan Can Tuerkcan: So in terms of measuring any of that directly in the course of that study directly, that won't be a part of it. However, with respect to the behavior of TTR and its decline, I think there will be a fair amount of information that we would expect to interpret. and one can look at the SIR and the A material and, you know, which is the relevant knockdown comparator. I, PTR levels are not knocked down by tapamitis, so it's a different kind of calculus that one might make. But, you know, I think one would expect to have a pretty good set of data to make some broad-based comparisons based on what we're expected to share.

John M. Leonard: Thank you so much for

Silvan Can Tuerkcan: Thank you so much for taking my questions. I'm going to come back on all the progress.

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Jay Olson: The next question comes from Jay Olsen with Ops. Please go ahead.

Jay Olson: Oh, thanks for taking the question. For the base editor system that you recently presented, will that base editor be used in both in vivo and ex vivo programs? And how do you plan to integrate that tool into your overall platform?

John M. Leonard: We're very excited about what particular sorts of applications base setters may be applied to. However, we see their greatest utility in the ex-vivo setting. It's not currently a part of the programs we've been talking about. If you saw the presentation that gave at Cold Spring Harbor, one of the things that we were very mindful of was the state of the art in terms of looking for stochastic off-target effects in the in vivo setting, and that's where we think there's additional work to be done for the field broadly. So in the near term, we think that the ex-vivo setting is probably the best place to use the base editor, but I'm sure work will continue, and that may change over time.

John M. Leonard: Great, and then maybe there is one follow-on question. For your upcoming presentation, ASGCT, what kind of pre-clinical data should we be looking for, and what are the gating factors to moving that program on to the next steps?

John M. Leonard: Well, at ASTCTCT, remember there are two presentations that we're making. One is a very detailed analysis of the off-target approach, which speaks broadly to what we do, so it doesn't necessarily relate to any particular program. The other presentation will be on extended information on, you know, the Alpha 1 antitripsin program. We're not talking yet about its status with respect to the pipeline and its candidacy, etc. We will have a third presentation where CSO will also be speaking broadly about gene editing and its clinical utilities, so there'll be some other insights. But we won't be talking about particular development candidates or changing their status. Great, thanks for taking the questions.

Jack Kilgannon Allen: Thank you. Your next question comes from Joe Allen with Baird. Please go ahead.

Jack Kilgannon Allen: Hi, thank you. Jack Allen here.

Jack Kilgannon Allen: Thanks so much for taking the question. We wanted to touch briefly on NTLA 2002, and we were wondering if you could talk a bit about your expectations for the trial as you move it toward the clinic. It's our understanding that there are a number of therapies already approved for HAE. How do you expect the magnitude of clinical benefit here as you move this into the clinic? And then, I know someone touched on this earlier, but you briefly mentioned that you may file an I-N-D or I-N-D equivalent for this program by the end of the year. Could you speak to the factors that are going to dictate the decision to go with an I&D or I&D equivalent? Is the NTLA 2001 data one of the factors that you're weighing in that decision? Thank you so much.

John M. Leonard: Yeah, just a couple of words about where we think 82002 can fit in the pharmacopoeia. We think that the modality that we have is ideally suited to heredary angioedema. It's certainly the case that advances have been made with respect to treating that condition. Either patients are treated as an attack occurs, patients don't like that, or they're prophylaxid with ongoing therapy. Remember, these are patients who are typically identified at the time of puberty or shortly thereafter.

John M. Leonard: So essentially, what you're talking about is lifelong therapy that is a very, very significant treatment burden and one that in some cases has become quite effective, and others far less so. So therapeutic opportunity clearly remains. Don't forget also that most effective therapies are extremely expensive, starting at over half a million dollars a year, with many patients spending over a million dollars a year for those same therapies. So whether it's meeting and exceeding the effect that others have achieved, whether it's dealing with the burden of treatment, or dealing with the significant pharmacoeconomic cost to the health care system.

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John M. Leonard: So, patients, we think that we have something to offer on every single front. With respect to the clinical trial and where we do it, we certainly look across all the work that we do, wherever it is, and whatever the drug is, and factor that in to how we think about what we're doing, how we're doing it, and where we're going to do it. And we would expect that to be a very central factor in our ultimate decision on where we carry this workout. Thank you so much.

Jack Kilgannon Allen: There is no time for further questions. I will now hand back to Lena for closing remarks. Great. Thank you all for joining us today and for your continued interest and support. We look forward to updating you on our progress. Have a wonderful day.

Joon So Lee: That does conclude our conference for today. Thank you for participating. You may now disconnect your lines.

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