Q1 2022 Intellia Therapeutics Inc Earnings Call

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Right.

Drew: Good morning, my name is Drew, and I will be your conference operator today. Welcome to the Intellia Therapeutics first quarter 2022 Earnings Conference Call. At this time, all participants are in a listen-only mode.

Good morning, My name is drew and I will be your conference operator today and welcome to the <unk> Therapeutics first quarter.

2022 earnings conference call at this time, all participants are in a listen only mode.

Drew: Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. If you require operator assistance, press star then zero.

Following the formal remarks, we'll open the call up for your questions. Please be advised that this call is being recorded at the company's request. If you require operator assistance Press Star then zero.

Ian Karp: At this time, I would like to turn it over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed. Thank you, operator. And good morning, everyone.

At this time I would like to turn it over to Ian Clark Senior Vice President of Investor Relations and corporate communications at <unk>. Please proceed.

Ian Karp: Welcome to Intellia Therapeutics' first quarter 2022 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company'

Thank you operator, and good morning, everyone. Welcome to Intel you Therapeutics first quarter 2022 earnings call.

Earlier this morning, and tell you issued a press release outlining the Companys progress this quarter as well as topics for discussion on today's call. This release can be found on the investors and media section of <unk> website at intaglio, TX Dot com.

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

Ian Karp: At this time, I would like to take a minute to remind listeners that during this call, Intellia Management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from the Intellia side are Dr. John Leonard, Chief Executive Officer; Dr. David Lebwohl, Chief Medical Officer; Dr. Laura Sepp Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights.

At this time I would like to take a minute to remind listeners that during this call and tell you management may make certain forward looking statements and ask that you refer to our SEC filings available at SEC Gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today and <unk> undertakes no duty to up.

Date, this information unless required by law.

Joining me from the Italian outside our Doctor, John Leonard Chief Executive Officer, Dr. David Loeb Walsh, Chief Medical Officer Dr.

Dr. Laura Sepp learned Dino Chief Scientific Officer, and Glenn Goddard Chief Financial Officer John .

John will begin with an overview of recent business highlights.

David will recap the recent update from our first in human study of N T. L. A 20 O one as well as progress across our clinical program.

Laura will then recap the company's R&D progress and Glenn will review <unk> financial results for the first quarter.

John will then offer some concluding remarks before we open the call up for Q&A with that I'll turn the call over to our CEO John .

Ian Karp: David will recap the recent update from our first in-human study of NTLA-2001, as well as progress across our clinical program. Laura will then recap the company's R&D progress, and Glenn will review Intellia's financial results for the first quarter. John will then offer some concluding remarks before we open the call up for Q&A. With that, I'll turn the call over to our CEO, John. Thank you, Ian, and thank you all for joining us this morning. Intellia is building full-spectrum genome editing and is deploying the industry's broadest and deepest toolbox, including novel editing and delivery, to harness the immense power of CRISPR-based technologies for in-vivo and ex-vivo therapeutic applications, each with the potential to revolutionize the future of medicine. At the beginning of this year, we laid out three core priorities.

Thank you Anne and thank you all for joining us this morning.

Until you were building full spectrum genome editing company.

Point, the industry's broadest and deepest toolbox, including novel editing and delivery solution our heart.

The immense power of CRISPR based technologies for in vivo ex vivo therapeutic applications, each with the potential to revolutionize the future of medicine.

John Leonard: Accelerating the clinical validation of our in-people pipeline, expanding our pipeline, and building on our scientific leadership by driving forward key platform innovation. We're making excellent progress. You can see some progress here.

At the beginning of this year, we laid out three core priorities.

Celebrating the clinical validation of our and people are expanding our pipeline and building on our scientific leadership driving forward platform innovation.

We're making excellent progress against these objectives during.

John Leonard: During the first quarter, we shared updated interim data from our landmark study of NTLA-2001. These results demonstrated that treatment was generally well tolerated and delivered rapid, consistent, dose-dependent reductions in serum TTR in people with hereditary ATTR amyloidosis with polyneuropathy. Among the three patients in the 0.7 mg per kg dose group, treatment with NTLA-2001 led to a mean serum TTR reduction of 86% by day 28. In six patients treated with a single 1 mg per kg dose, a 93% mean and 98% maximum reduction was achieved by day 28. Further, the reduction of PTR levels has been sustained through the observation period, providing the first evidence that a single dose CRISPR investigational therapy may provide a lifelong effect.

During the first quarter, we shared updated interim data from our landmark study of MTO late 'twenty one.

These results demonstrate the treatment was generally well tolerated and deliberate rapid consistent dose dependent reductions in serum PTR and people with hereditary <unk> amyloidosis with Polyneuropathy.

Among the three patients in the <unk> seven milligrams per kilogram dose group three members and kill a 20th one led to a mean savi teach you a reduction of 86% at day 28 six.

Six patients treated with single one Meg per kg dose.

3% mean and 98% maximum reduction was achieved by day 28.

Further the reduction of PCR levels, it's been sustained through the observation period, which provides the first evidence that a single dose Christopher investigational therapy may provide a lifelong effect.

John Leonard: David will review these data in greater detail, including selection of the fixed dose to be evaluated and the expansion portion of the polyneuropathy arm. We plan to present additional data from the Polyneuropathy Arm of the Study at the upcoming EASL International Liver Congress being held in June. In addition, we hope to share the first interim data from the cardiomyopathy arm later this year. These updated data will not only bolster our confidence in MTLA-2001 as a potential treatment for ATTR amyloidosis but will also reinforce our belief in the power of our platform for in vivo keen editing.

David will review these data in greater detail, including selection of a fixed dose to be evaluated in the expansion portion of the polyneuropathy or <unk>.

And at present additional data from the Polyneuropathy arm of the study at the upcoming evil International liver Congress being held in <unk>.

We hope to share the first interim data from the cardiomyopathy are later this year.

These updated data not only bolster our comprehensive manipulate 20th one as a potential treatment for APC are amyloidosis.

Also reinforce our belief in the power of our platform for people to gene editing.

John Leonard: Notably, we look forward to sharing the initial clinical data from our second in vivo program, Intellia 2002 for HAE, later this year. Switching to our ex vivo pipeline, in March, we dosed the first patient in our clinical study of NTLA-5001 for the treatment of AML. All together, the modular nature of our platform is on full display as we've advanced and expanded our pipeline considerably in both the InVivo and ExVivo settings and initiated multiple strategic business development collaborations that extend the reach of our technology beyond our core focus. Finally, earlier this week, we were pleased to welcome Munna Banji to our Board of Directors.

Notably we look forward to sharing the initial clinical data from our second in vivo program until the 20th two rates I E. Later this year.

Switching to our ex vivo pipeline in March we dosed the first patient in a clinical study of <unk> for the treatment of AML.

Altogether, the modular nature of our platform is on full display as we've advanced and expanded our pipeline considerably.

In vivo index vivo settings, and initiated multiple strategic business development collaborations that extend the reach of our technology beyond our core focus.

Finally earlier this week, we were pleased to welcome <unk> to our board.

John Leonard: She brings over three decades of experience in commercial strategy and market access, and her History of successfully Navigating Global Healthcare Systems to Improve Patient Access in Innovative Medicine will be invaluable to Intellia. In addition, her appointment is an important step forward as we believe that it's essential that our board members represent diverse backgrounds and have experience and skills in areas that are most relevant to the company's strategic plan. With that introduction, I'll hand the call over to our Chief Medical Officer, David Lebwohl, who will review the NLA-21 data in greater detail and detail progress across our pipeline. David?

Correct.

She brings over three decades of experience in commercial strategy and market access our history of successfully navigating global health care systems to improve patient access innovative medicines will be invaluable to until you.

In addition, our appointment is an important step forward as we believe that it's essential that our board members represent diverse backgrounds and have experiences and skills in areas that are most relevant to the company's strategic plans.

With that introduction I'll hand, the call over towards Chief Medical Officer, David Loeb.

We'll review the until late 'twenty, one data in greater detail and detailed progress across our pipeline.

Got it.

David Lebwohl: Thanks, John, and welcome, everyone. I'll begin with a review of 2001 and our recent data update. We are developing 2001 as a potential best-in-class, one-time treatment option for people living with ATTR amyloid. Last June, we published landmark data in the New England Journal of Medicine from our ongoing phase one trial of 2001, demonstrating our ability to deliver our in vivo CRISPR candidate to the intended tissue and precisely edit the target gene. In February, we shared updated interim data and were highly encouraged by the results, which have begun to answer fundamental questions about our investigational genomic medicine.

Thanks, John and welcome everyone.

David Lebwohl: The update included interim data from all 15 patients treated across the four dose escalation cohorts in the completed part one of the polyneuropathy arm. Key insights from the ongoing phase one include that 2001 was generally well tolerated at all dose levels. It was a dose-response relationship that showed that higher doses yielded deeper serum TTR reduction. Importantly, these reductions occurred rapidly, with maximal reductions achieved by day 28.

Begin with review of 'twenty, one and our recent data update.

We are developing 21 as a potential best in class onetime treatment option for people living with H T. T. R amyloidosis.

Last June we published landmark data in the New England Journal of Medicine from our ongoing phase one trial of 21, demonstrating our ability to deliver our in vivo CRISPR candidates to the intended tissue and precisely edit the target gene.

In February we shared updated interim data and we're highly encouraged by the results, which have begun to answer fundamental questions for our investigational genomic medicine.

The update included interim data from all 15 patients treated across the board dose escalation cohorts and the completed part one of the Polyneuropathy arm.

Key insights from the ongoing phase one include the 20th one was generally well tolerated at all dose levels.

It was a dose response relationship which showed that higher doses yielded deeper CRM GTR reductions.

Importantly, these reductions occurred rapidly with maximal reduction achieved by day 28.

David Lebwohl: Treatment with one milligram per kilogram of 201 led to a 93% mean and a 98% maximum reduction in serum TTR by day 28. Finally, mean reductions were maintained through the observation period, ranging from 2 to 12 months following a single dose across all dose levels. This finding is consistent with our preclinical modeling and provides early validation that these reductions are durable. Based on previously published data, it has been demonstrated that there is a strong correlation between the degree of protein reduction and clinical outcomes in both ATPR and other forms of amyloid doses.

Treatment with one milligram per kilogram 21 led to a 93% and a 98% maximum reduction in serum T. T. R by day 28.

And finally mean reductions were maintained through the observation period, ranging from two to 12 months following a single dose across all dose levels.

This finding is consistent with our preclinical modeling and provides early validation that these reductions are durable.

Based on previously published data that's been demonstrated that there is a strong correlation between the degree of protein reduction and clinical outcomes in both H T T R and other forms of amyloidosis.

David Lebwohl: With the deep and persistent levels of TTR reduction we have seen thus far, 2001 has the potential to halt and perhaps even reverse the course of this disease. After completing the dose escalation portion of the polyneuropathy arm, Intellia is now evaluating a sixth dose of 80 milligrams in part two of the phase one study, which is expected to deliver a similar exposure to one milligram per kilogram. We are happy to share that we recently dosed the first patient in the Single Dose Expansion cohort.

With the deep and persistent levels of GTR reduction, we have seen thus far 'twenty, one has the potential to halt and perhaps even to reverse the course of this disease.

I'm conflating the dose escalation portion of the Polyneuropathy arm and Kelly is now evaluating a fixed dose of 80 milligrams in part two of the phase one study, which is expected to deliver a similar exposure to one milligram per kilogram.

We are happy to share that we recently dosed the first patient in the single dose expansion cohort.

David Lebwohl: We plan to present longer-term follow-up data from the dose escalation portion of the polyneuropathy arm, as well as PK data supporting our fixed-dose selection at the Easel International Liver Congress, which is taking place June 22-26. In the cardiomyopathy arm of the study, we continue to dose patients in separate dose escalation cohorts at 0.7 and 1 milligram per kilogram.

We plan to present longer term follow up data from the dose escalation portion of the Polyneuropathy arm as well as PK data supporting our fixed dose selection.

The easel International liver Congress, which is taking place June 'twenty to 'twenty six.

And the cardiomyopathy arm of the study we continue to dose patients in separate dose escalation cohorts at 0.7, and one milligram per kilogram.

David Lebwohl: Following results from the dose escalation portion, we then plan to move to the dose expansion stage. As John noted earlier, our goal is to share interim data from the cardiomyopathy arm in the second half of this year. We expect to complete enrollment in both arms of the study by year end. Based on the activity and safety data we have observed, we expect to advance clinical development toward future studies for both forms of ATTR amyloidosis.

Following the results from the dose escalation portion, we then plan to move to the dose expansion stage.

As John noted earlier, our goal is to share interim data from the cardiomyopathy arm in the second half of this year, we expect to complete enrollment in both arms of the study by year end.

Based on the activity and safety data, we observed we expect to advance clinical development towards future studies for both forms of H T. T. R amyloidosis.

David Lebwohl: This will include ongoing and additional engagements with regulatory agencies, including the U.S. FDA. Turning now to 2002, our investigational therapy for the treatment of hereditary angioedema or HAE. People with HAE experience recurrent, unpredictable, and painful types of swelling across multiple tissues.

This will include ongoing and additional engagements with regulatory agencies, including the U S. D. A.

Turning now to 20 O to our investigational therapy for the treatment of hereditary angioedema or H E E.

People with Asia, you experienced recurrent unpredictable and painful types of swelling across multiple tissues.

David Lebwohl: While there are approved acute and prophylactic therapies for HAE, the treatment burden on patients remains significant. To that end, we're applying our modular LNP delivery system to knock out the KLKB1 gene in the liver to permanently reduce plasma calocrine protein inactivity. As a point of reference, a 60% reduction in pre-calocrine activity has been associated with a clinically relevant reduction in HAE attacks. To date, in non-human primates, Intellia has demonstrated our ability to achieve greater than 90% reduction of both pre-talcine protein and activity after a single dose, which remained durable through a two-year observation period.

While there are approved acute and prophylactic therapies for H I E. The treatment burden on patients remain significant.

To that end, we are applying our modular LNP delivery system to 20 O two to knock out the K O K B, one gene in the liver to permanently reduce plasma calvert crime protein and activity.

As a point of reference a 60% reduction in pre calc client activity has been associated with a clinically relevant reduction in H AE attacks.

To date in nonhuman primates, and Kelly has demonstrated our ability to achieve greater than 90% reduction of both pre <unk> protein and activity. After a single dose which remained durable through a two year observation period.

David Lebwohl: These results, if achieved in humans, highlight the potential of 2002 to provide continuous suppression of calocrine activity and address the significant treatment burden associated with currently available therapies for HAE patients. We continue to progress the dose escalation portion of our Phase 1-2 study for 2002. We've completed dosing in the first cohort, evaluating 2002 at a fixed dose of 25 milligrams and have advanced to the second dose level at 75 milligrams. We anticipate presenting initial interim data from this trial during the second half of the year, with these results expected to characterize the emerging safety and activity profile of 2002 and potentially demonstrate preliminary proof of concept for this program.

These results achieved in humans.

The potential of 20 O two to provide continuous depression with Calvin Klein activity and address the significant treatment burden associated with currently available therapies for H H E patient.

We continue to progress the dose escalation portion of our phase one two study for 20 O two.

We've completed dosing in the first cohort evaluating 20 O two at a fixed dose of 25 milligrams and have advanced to the second dose level at 75 milligram.

We anticipate presenting initial interim data from this trial during the second half of the year with each results expected to characterize the emerging safety and activity profile of 20 O two and potentially demonstrate preliminary proof of concept for this program.

David Lebwohl: Moving on to our ex vivo pipeline. Our ex vivo approach is designed to produce homogeneous, robust cell products that epitomize the patient's natural immune system for the treatment of cancer and autoimmune disease. For our first program, 50-01, we are employing a TCR-based approach targeting the Wilms Tumor 1 intracellular antigen, which is overexpressed in more than 90% of patients with AML, regardless of the mutation subtype.

Moving on to our ex vivo pipeline.

Our ex vivo approaches designed to produce homogeneous robust sell products that epitomize the patient's natural immune system for the treatment of cancer and autoimmune diseases.

For our first program 50 are one we are employing a TCR based approach targeting the wilms tumor one intracellular antigens, which is over expressed in more than 90% of patients with AML, regardless of the mutation subtype.

Laura Sepp Lorenzino: In March, we dosed our first patient in the Phase 1-2A study and also received orphan drug designation from the FDA for the treatment of AML. We continue to enroll patients in the ongoing study, and later this year, we expect to provide an update on the progress of the trial. I'll now hand over to Laura, our CSO, who will provide updates on our platform and R&D efforts. Thanks, David.

In March we dosed, our first patient in the Phase <unk> study and also received orphan drug designation from the FDA for the treatment of AML.

We continue to enroll patients in the ongoing study.

And later this year, we expect to provide an update on the progress of the trial.

I'll now hand over to <unk>, our CFO , who will provide updates on our platform and R&D efforts.

Laura Sepp Lorenzino: I'll start with our in vivo pipeline. We're now advancing two wholly-owned development candidates for the treatment of Alpha-1 and Atribs Indeficiency, or AATD. For AATD, our modular platform provides us with the optionity for patient-tailored treatments relevant to the particular disease phenotype. This includes NTLA-30.01, our gene insertion candidate for the lung disease, and NTLA-20.03, a knockout candidate for the liver disease.

Thanks, David I'll start with our in vivo pipeline. We're now advancing two wholly owned development candidates for the treatment of women being treated seen deficiency or a APB.

A a PD out a bunch of a platform provides us the optionality for patients tailored treatment relevant to the particular niches seem to date.

This includes India later, when allergy nutrition candidates.

D C and MTN eight when you're sitting in a good candidate before they leave.

Laura Sepp Lorenzino: We're now progressing IND-enabling activities for both candidates and expect to file an IND or equivalent application for NTLA-3001 next year. Stay tuned for more updates as we expect to nominate at least one new additional in vivo development candidate before the end of the year. Moving to our ex vivo pipeline, earlier this year, we announced the nomination of MDLA-6001, an allogeneic CAR T candidate designed for the treatment of CD30-expressing hematologic cancer. It is the first internally developed candidate using our proprietary allogeneic cell engineering platform.

We're now progressing I M D M avium activities for both group meetings and expect to find in I N D link with them its application for N P and eight tier one next year.

Stay tuned for more updates that we expect to nominate at least one new ABC in vivo development candidate before the end of the year.

Moving to our ex vivo side.

This year, we announced elimination MD&A 61, an allogeneic car T candidate designed for the treatment of CD 30 expenses hematologic cancers.

He says first internally developed candidates using our proprietary allogeneic cell engineering platform.

Laura Sepp Lorenzino: At the Keystone Symposium's Precision Genome Engineering Conference, we presented preclinical data that our allogeneic solution created immune-evading T cells with high viability, potency, and persistence, and it's readily deployable for DCRT and CAR T cell therapy. These data highlight that NTLA-6-TL1, which incorporates our LEAD-CD3-DCAR contract, showed complete tumor regression and protection from tumor re-challenge in a T-cell lymphoma model.

And Keystone Symposium presentation genome engineering countries, we presented preclinical data and our allergy need solution created debating T cells with high viability potency and persistence and he's really deployable for D. C I T and T cell candidate.

These Nathan Hi, David that MTN late 16.

This incorporates our D. C. D. 30 concludes check showed complete tumor regression and protection from tumor with Chinese <unk> T cell lymphoma model. We're now beginning I M D, enabling activities for M. D N a 61.

Laura Sepp Lorenzino: We're now beginning IND-enabling activities for NTLA-6-TL1. With the strength and breadth of our CRISPR-based platform, our strategy is to partner with others who possess complementary capabilities to maximize the value of our platform and gain future product rights to innovative therapies. This year, we've already completed two strategic collaborations, the first one with Kiberna, which is focused on advancing an allo-CD19 CAR-T cell candidate for select autoimmune diseases, and the second one with ONK Therapeutics, which is focused on developing CRISPR-edited NK cell therapies for cancer.

We the strength and breadth of our CRISPR based platform our strategy is to partner with others, who protests complementary capabilities to maximize value from our platform and game future public Reits to innovative therapies.

You see it maybe completed two strategic collaborations the first one with high burden, which is focused on advancing and I don't see the main P. E. T. So trying to get a fortunate autoimmune diseases.

The second one we only in case of that business, which is focused on developing CRISPR edited NK cell therapies for cancer.

Laura Sepp Lorenzino: In total, across our business development transactions over the past 12 months, we have now gained options for commercial rights for up to seven additional therapeutic candidates. In addition, we have added new technologies to our leading toolbox, such as DNA writing, that are complementary to our existing CRISPR-Cas9 and base editing capabilities. We continue to pursue additional capabilities that will allow us to employ the best and most appropriate tool for each therapeutic application. Finally, to support our growing pipeline, we have entered into a lease agreement to build a GMP manufacturing facility in Waltham, Massachusetts.

Across our business economic transactions from the past 12 months, we have now gained options for commercial rights. We're at two seven and they should be they can be like.

In addition, we have added new technologies to our leading toy box that you can be any ranking that are complementary to our existing CRISPR Cas nine and basically anything capabilities.

We continue to pursue additional capabilities will allow us to employ the best and most appropriate tool for each therapeutic application.

Finally to support our growing pipeline, we have entered into a lease agreement to build a GMP manufacturing facility in Boston, Massachusetts.

Glenn Goddard: This new facility will provide us with significant manufacturing capacity to support preclinical through commercial production of Intellia's investigational therapy. Now, I hand over the call to Glenn, our CFO, who will provide an overview of our first quarter financial results. Thank you, Laura, and good morning, everyone. Intellia continues to maintain a strong financial position to support our plans, and in particular, over the past few months, we've delivered on our strategy to expand our pipeline in a capital-efficient manner. Our cash, cash equivalents, and marketable securities were approximately $995 million as of March 31, 2022, compared to $1.1 billion as of December 31, 2021.

New facility will provide us with significant manufacturing capacity to support preclinical through commercial production of Italian investigation of canopies.

Well now open the call to Glenn our CFO will provide an overview of our first quarter financial results.

Glenn Goddard: The decrease was driven by cash used to fund operations of approximately $95.7 million and the acquisition of Rewrite Therapeutics for $45 million. The decrease was offset in part by $38.9 million in net proceeds raised from the company's ATM program and $8.4 million in proceeds from an employee-based stock plan. Our collaboration revenue increased by $4.8 million to $11.3 million during the first quarter of 2022, compared to $6.4 million during the first quarter of 2021.

Thank you Laura and good morning, everyone and.

Glenn Goddard: The increase was mainly driven by our joint venture with Avancel. Our R&D expenses increased by $93.8 million to $133.1 million during the first quarter of 2022, compared to $39.3 million during the first quarter of 2021. This increase was driven by $56 million of expenses related to the acquisition of free rides, which includes a $45 million upfront payment and $10.5 million related to a potential stock-based earn out payment. The remaining $37.8 million was driven by the advancement of our LEAD program and the continued expansion of our development organization.

<unk> continues to maintain a strong financial position to support our plans and in particular over the past few months, we've delivered on our strategy to expand our pipeline in a capital efficient manner.

Glenn Goddard: Our G&A expenses increased by $8.8 million to $22.4 million during the first quarter of 2022, compared to $13.6 million during the first quarter of 2021. This increase was mainly related to employee-related expenses, including stock-based compensation of $5.3 million.

Our cash cash equivalents in marketable securities were approximately $995 million as of March 31, 2022, compared to $1 $1 billion as of December 31, 2020 one.

The decrease was driven by cash used to fund operations of approximately $95 $7 million.

And the acquisition of rewrite therapeutics for $45 million.

Decrease was offset in part by $38 9 million in net proceeds raised from the company's ATM program.

And $8 $4 million and proceeds from employee based stock plans.

Our collaboration revenue increased by $4 $8 million to $11 $3 million during the first quarter of 2022.

<unk> to $6 $4 million during the first quarter of 'twenty or 'twenty one.

The increase was mainly driven by our joint venture what's happened so.

Our R&D expenses increased by $93 $8 million to $133 $1 million during the first quarter of 2022 compared to $39 $3 million during the first quarter of 2020 one.

This increase was driven by $56 million of expense related to the acquisition of free right.

Which includes a $45 million upfront payment and $10 $5 million related to a potential stock based earn out payment.

The remaining $37 $8 million was driven by the advancement of our lead programs and the continued expansion of our development organization.

Our G&A expenses increased by $8 $8 million to $22 $4 million during the first quarter of 2022 compared to $13 $6 million during the first quarter of 2021.

This increase was mainly related to the two employee related expenses, including stock based compensation of $5 $3 million.

Finally, we expect our cash balance to fund our operating plans beyond the next 24 months.

With that I will turn the call back over to John for closing remarks.

John Leonard: Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. With that, I will turn the call back over to John for closing remarks. Thank you, Glenn. We're already making significant progress against our 2022 strategic priority. First, we're advancing robust pipeline, including BACOLI-owned and partnered programs, now with multiple programs. Next, we're expanding into new therapeutic areas with continued investment in platform innovation. Further, we're strategically licensing our technologies to accelerate development programs outside our key areas.

Thank you Glenn we're already making significant progress against our 2022 strategic priorities.

First we are advancing a robust pipeline, including both wholly owned and partnered programs now with multiple programs in the clinic.

Next we're expanding into new therapeutic areas with continued investment and platform innovation.

Further we're strategically licensing our technologies to accelerate development programs outside of key areas of focus and importantly, we remain in a position of financial strength that enables us to realize our vision for Italian.

Drew: And importantly, we remain in a position of financial strength that enables us to realize our vision for Intellia. With that, we'd be happy to answer any questions about our pipeline and platform. Operator. We will now begin the question and answer session. To ask a question, you may press star and then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys.

With that we'd be happy to answer any questions about our pipeline platform.

Operator.

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 keys to withdraw your question. Please press Star then two.

Svetlana Melnikar: To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. Our first question comes from Svetlana Melnikar of Piper Sandler. Please go ahead. Good morning.

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

The first question comes from sweating, though another car.

Sandler. Please go ahead.

Svetlana Melnikar: Thanks for taking my questions. So, the first one is, with the fixed dosing regimen, are there any concerns in lighter patients who might get exposed to more than one mcpercig dose, especially related to safety? And then I will follow up. David, do you want to give your views on how we think about the fixed-dose thing? Yeah, no, thank you.

Great. Good morning, Thanks for taking my questions. So first one is with the fixed dosing regimen out a bit any concerns and likelihood of patients who might get exposed to what more than one kick those especially when they pick the safety.

And then I have a follow up.

David do you want to give.

If your views on how we think about the fixed dosing and safety.

David Lebwohl: The fixed doses were based on looking at all the data that we had as we were going forward to part one. So, you recall in part one, what we saw and reported in February were very deep reductions, 93% average reduction in six patients, and that at that point, it was durable with variable follow-up from 2 to 12 months. We also then had the PK from this work.

Yeah no. Thank you get a fixed dosing was was based on looking at all the data that we had a as we were going forward to part one.

So you recall in part one what we saw on reported in February we're very deep reductions, 93% average reduction in six patients.

And and that at that point it was durable with variable follow up from two to 12 months.

We also then have the PK from this work.

David Lebwohl: And what it showed is that the exposure of patients was not significantly affected by the weight of the patient, and we will be showing you more details of that in our upcoming presentations at ease. What that means, though, is that small patients and larger patients essentially are experiencing the same exposure of the drug. We think this is related to the fact that no matter how much your weight is, depending on fat or not, your liver size is similar.

And what it showed is that the exposure of patients was not significantly affected by the weight of the patients.

And we won't be I'm, showing you more details of that in our upcoming presentations of diesel.

So what that means though is that small patients and in larger patients essentially are are experiencing the same exposure of drug. We think this is related to the fact that the and no matter how much what.

What your weight is depending on sat or not that your liver size is similar and that's really the target of Archrock and that's and that's where the exposures coming out.

David Lebwohl: And that's really the target of our drug, and that's where the exposure is coming from. So what we expect going forward, and this will be tested in part two, of course, we want to confirm what we found from part one, is that we will see the same type of deep reductions, good safety, and then be able to move forward to further study. And then one follow-up is, although it's a little bit premature to discuss, but do you have any thoughts on the upsized and extended duration trial for INS's cardio transform trial and its implications for future Intellia strategies for patients with pivotal cardiomyopathy?

So what we expect going forward and this will be tested in part two of course, we want to confirm what we found from part one is that we will.

We will see the same type of deep reductions the good safety and and then be able to move forward to further studies.

Got it and then one follow up although like electric but premature to discuss but.

Do you have any talks on the Upsized and extended duration trial I emphasis cardio transform trial.

And its implications for future Internet strategy for photo cardiomyopathy trial.

David Lebwohl: Yeah, we did we did look at the announcement and some of the things they said about it. What they're saying is it's not based on any data they really know from their trial. They're really looking to have a more robust trial. What's important to us as it moves forward is, you know, we are going to learn from some of the ongoing trials. That one will come a little bit late for the trials we're going to do. But certainly the trials from Bridgebile and from Amylam will help inform our trial as we as we move forward. Great.

Yeah. We did we did look at the announcements and some other things they set up out at what they're saying is it's not based on any data. They really know from their trial. They are really looking to have a more robust trial.

What's important to us is as it moves forward is.

We we are going to learn from some of the ongoing trials that one will come a little bit late for the trials were going to do but certainly the trials from bridge bile and from an island will help inform our trial as we as we move forward.

Great. Thank you for taking my questions.

Yeah.

Svetlana Melnikar: Thank you for taking my question. The next question comes from Maury Raycroft with Jeffreys. Please go ahead. Hi, good morning.

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

Maury Raycroft: Congratulations on the progress and thanks for taking my questions. I was going to ask one about HAE. I'm wondering if you can elaborate on what preliminary proof-of-concept data could look like in the second half of this year, and have you decided to dose higher than 75 mg fixed, or do you know at this point that that's not needed? There are a lot of questions in there. We can probably talk a little bit more about dosage as the year goes on.

Hi, good morning, Congrats on the progress and thanks for taking my questions.

I was going to ask one on H H E. I'm wondering if you can elaborate on what preliminary proof of concept data could look like second half of this year and have you decided to dose higher than 75 makes fixed or do you know at this point that that time needed.

Boy, there's a lot of questions in there.

We can probably talk a little bit more about the dosing as the year goes on but maybe David what do you have in store for data releases and how are you thinking about the progress of that trial.

Maury Raycroft: But maybe, David, what do you have in store for data releases and how are you thinking about the progress of that trial? So for HAE, I think we've said a lot of times, this is using our modular approach, so what's important here is we could learn from what we did in 2001 and bring it to 2002. One of those important lessons is how safe the product is at early doses.

Yeah, So free Chi I think we've said a lot of times. This is I'm using.

Using a modular approach so what's important here is we could learn from what we did in 'twenty, one and bring up to 20 O two.

One of those important lessons is what's the safety of the product.

Is that the early doses and with that we did start it in at a higher dose. We started at 25 milligrams, which is basically equivalent to the 0.3 milligram per kilogram dose.

David Lebwohl: And with that, we did start at a higher dose; we started at 25 milligrams, which is basically equivalent to the 0.3 milligram per kilogram dose that was used in the 2001 trial. We will be bringing forth data at the next dose level, as you said, at 75 milligrams, which would be similar to the higher dose, the highest dose that we treated in the 2001 trial. So we do expect this to be safe based on what we know from 2001.

That was used in the 20th one trial.

We will be bringing forth data in and then the next dose level is as you said was 75 milligrams, which would be similar to the to the higher dose at the highest dose that retreated into 'twenty. One trial. So we do expect this to be say, it's based on what we know from from 'twenty, one and what we expect.

David Lebwohl: And what we expect to see in terms of what we could report in the second half of the year as proof of concept is a decrease in the biomarkers, and particularly pre-columcrine levels and activity, are both being looked at in this trial. And that, as we've seen with previous and other compounds, that is very likely to be associated with a decrease in attack rate, actually a very substantial one. Thank you for watching! I think we may have lost David's audio somewhere.

To see in terms of what can we support in the second half of the year and proof of concept is seeing a decrease in the biomarkers.

And particularly pre collar crime levels and activity are both being looked at in this trial.

As we've seen in previous and other compounds that is very likely to be associated with a decrease in our tax rate.

Actually a very substantial.

Okay.

Yeah.

I think we may have lost Dave.

Davids.

John Leonard: I can just finish up. Maury, I think that we'll be in a position to share that, and we'll apply the same principles that we've applied in the past in terms of making those judgments about, you know, significant, interpretable, and consistent. And if we're in a position to share attack rates from a clinical point of view, we can't, you know, guarantee that at this point, because it ties down to having sufficient time to We will certainly, if we're in a position to share that, try to share that as well. I got it.

Audio there I can just finish up.

Laurie.

<unk>.

You know for sure it will be in a position where we can talk about the effect on the biomarker and I think that will be in a position to share that.

And we will apply the same principles that we've applied in the past in terms of making those judgments about you know significant interpretable and consistent.

And if we're in a position to share attack rates from a clinical point of view we can't.

Guarantee that at this point is the tightest stone to having sufficient time to make those observations and the characteristics of the patients.

We will certainly if we're in a position to share that we'll try to share that as well.

Maury Raycroft: That's really helpful. Maybe a quick follow-up, if you can talk about the types of HAE patients that you're enrolling into the study as far as baseline attack rates are concerned at this point, or, Well, attack rates are not really the primary determinant. There's a threshold level. I mean, we want to have everybody with, obviously, the disease diagnosed. And there's, we're not requiring a high attack rate to get in.

Got it that's really helpful and maybe a quick follow up if you can talk about the types of patients that you're enrolling into the study as far as baseline attack rates at this point or.

John Leonard: But, you know, these are all attack rates that, over the course of a, I think it's a four month observation period, they should be expected to have had several instances of attacks within that time period. So that's why you need to have a baseline and then, you know, sufficient time to observe the patients thereafter.

Well the attack rates is not really the primary determinants, there's there's a threshold level.

I mean, we wanted to have everybody with obviously the disease diagnosed and there's a we're not requiring a higher tac rate to get in.

But you know.

These are all attack rates that have over the course of a I think it's a four month observation period.

They should be expected of had several instances of attacks and within that time period and so that's why you need to have a baseline and then you know sufficient time to observe the patients thereafter.

Daegon Ha: Okay, thanks for taking my question. Sure, thank you. The next question comes from Daegon Ha of Stiefel. Please go ahead. Great. Good morning.

Got it okay. Thanks for taking my questions.

Daegon Ha: Thanks for taking our questions. I'll add one more question on 2002 if I can. And it's a two-part question. So I think this is actually the first time we're hearing about the 25 and 75 MIG, if I'm not mistaken. So the first part is, since your cohort will be, or at least looks like, N of 3 to 6 per cohort, are you able to comment on what N was in the first cohort that just completed and what determines the final N in each of these cohorts?

Sure. Thank you.

The next question comes from Dae Gon Ha of Stifel. Please go ahead.

Daegon Ha: And secondly, when we look at 25 and 75 MIG fixed doses, there was the NHP data that you presented at Quad AI last year. What dose level would this correspond to when we think about allometric scaling?

John Leonard: And I've got a follow-up. Thank you. So, this is a three-part question.

Great. Good morning, Thanks for taking our questions I'll add one more question on 2002, if I can and it's a two part question.

So I think this is actually the first time, we're hearing about the 25 and 75 Meg if I'm not mistaken. So first part is since your cohort will be or at least looks like and it's three to six per cohort are you able to comment on what Ann was in the first cohort that just completed and what determines the final end and are in each of these.

Cohorts and secondly, when we look at 25 and 75 Meg fixed dosing there was the NH P data that you presented at Coty I last year, what dose level. What this correspond to when we think about allometric scaling and I've got a follow up thank you.

John Leonard: With respect to the dosing of 25 and 75 fixed doses that we just referred to, David spoke to how that relates to the PTR program. And, you know, that is all derived from looking at the preclinical results and drawing heavily from what is the highly, highly related dosing form that we're using in TTR. So, you know, a simple rule of thumb. If you want to try to extrapolate to the animals, it's more complicated than this, but if you divide by approximately three, you'll get a similar sort of effect.

So a three part question.

With respect to the dosing of 25 and 75 fixed dose that we just referred to.

David spoke to how that relates to the TCR program.

And.

That is all derived from looking at the preclinical results.

And drawing heavily from what is the highly highly related dosing form that we're using in T. T ours. So.

You know a simple rule of thumb, if you want to try to extrapolate to the animals.

It's more complicated than this but if you divide by approximately three youll get to a similar sort of effect if theres more complications in that because you've got to take into consideration the activity of the guide et cetera, but for the purposes of discussion. That's that's how I would do it if I were looking from animals to humans.

John Leonard: There's more complications than that because you've got to take into consideration the activity of the guide, et cetera, but for the purposes of discussion, that's how I would do it if I were looking from animals to humans. With respect to how large the cohorts are, the rules are, you know, as we've done with the TTR program, one starts with an N of three if a dose-limiting toxicity is reached, that drives an expansion to an additional three patients, and that would determine the final number of patients, the final capped number of patients within a dose cohort, um and uh repeat your second question, I think that's actually all of it, so I can just go on into the follow-up question, which is the LNPs, when we think about 2003 and 3001 going after either the liver or the lung, I guess just curious on the 3001, is it correct to assume that the LNP used here is going to be characteristically different from the ones used in 2001, 2002, and presumably 2003?

With respect to how.

Largely cohorts are the rules are as we've done with the TCR program.

When it starts with an N of three if a dose limiting toxicity is reached.

That drives an expansion to an additional three patients.

And that would determine the final number of patients the final capex number of patients whether or not those are.

Cohort.

And Ah repeat your second question, Mike I think that's actually all of all of it. So I can just go out into the follow up question, which is the Ellen piece. When we think about 2003 and 3001 going after either of the liver or the long I guess just curious on that.

3001 is it correct to assume that the L. N. P used here is going to be characteristically different from the ones used in 2001, and 2002, and presumably 2003 and win I guess in the prepared remarks, you alluded to another in vivo candidate selection before year end 'twenty, two I guess does that too.

John Leonard: And when, I think, in the prepared remarks, you alluded to another in vivo candidate selection before year end, 22, I think the 3001 progress imply that a lung program might be up next. Thank you very much.

<unk> 3001 progress.

Imply that had long program might be up next thank you very much.

Yeah.

John Leonard: Well, one of the things to remember is that all of the work that we're doing that targets the liver, whether it's 2001, 2002, 2003, or the 3001 program, which is hybrid, it has an LMP and an AAV component. All of this goes back to the modular approach that we've highlighted from the beginning, which starts with essentially the same limpid shell, and the cargo elements, which consists of mRNA, and the So... With respect to the LNP, across all those programs, there is just a very, very extensive similarity, and I would think about it that way.

Well one of the things to remember is that all of the work that we're doing that targets the liver, whether it's 2001 2002 2003.

Or the 3001 program, which remembers is hybrid it has no lumpy in an AAV component.

All of this goes back to the modular approach that we've highlighted from the beginning which starts with essentially the same lipid shell and the cargo elements, which consists of M. R mrna and the guide RNA.

Are all the same with the exception of the last 20 nucleotide or so of the guide RNA.

So.

With respect to the inland P across all of these programs.

There is.

Just very very extensive similar and I would think about it that way.

John Leonard: With 30.01, we're bringing AAV into the equation as a way of delivering the transgene to be inserted. So that's the distinction, and the way we think about 2003 or 2003 and 3001 is that, really, they both target aspects of alpha-1 antitrypsin deficiency, but really independent of each other, 2003 targets the gene itself and eliminates the production of the defective protein. And 3001 provides a source of wild-type protein to foresee the progression of lung disease.

With 31, we're bringing in AAV into the equation as a way of delivering the transgene to be inserted so that's the distinction.

And.

The way, we're thinking about 2003 or 'twenty, three and 301 is that well they both target aspects of Alpha one antitrypsin deficiency, there really independent of each other 20th III targets, the gene itself and eliminates the you know.

The production of the defective protein and 31 provides a source of wild type protein to forestall progression of lung disease. So for simplicity sake, we treat them differently.

John Leonard: So, for simplicity's sake, we treat them differently, but we would be in a position to merge them at the end within a single patient if we think that that's appropriate. Excellent. Thank you so very much.

But we would be in a position to merge them at the end within a single patient if we think that that's warranted.

Excellent. Thank you so very much.

Sure.

Salveen Richter: And in the interest of time, we kindly ask that you keep yourself to one question. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Good morning.

And in the interest of time, we kindly ask that you.

Keep yourself to one question.

The next question comes from solving Richter with Goldman Sachs. Please go ahead.

Okay.

Salveen Richter: Thanks for taking my question. Just on the HAU program as well, if you do see an optimal profile, where do you see it fitting into the treatment paradigm, given the current options here for these patients? David, do you want to? I think you're back. We lost David's audio for a minute there.

Good morning, Thanks for taking my questions. Some 18 program as well.

Optimal profile, where do you see it.

But the treatment paradigms.

The current option care for these patients.

David Lebwohl: But David, where do you think this treatment fits into the treatment of HAE? Thank you, and I'm sorry for my technical disclosures this morning. So this treatment, of course, would be a prophylaxis. What we'd expect to see reductions, and what's been seen with other compounds in the 60 to 80% range, is that you would have a greater than 90% reduction in attacks, and perhaps even better as you get to those higher levels.

David do you want to I think your bet unless David its audio for a minute there but David.

Where do you think this treatment fits into the.

Treatment of HCV patients.

Yeah, Thank you and I'm sorry for my technical support this morning.

So this this treatment of course would be a prophylaxis, what we'd expect to see getting reductions and what's been seen with other compounds in the 60% to 80% range is that you would have a greater than 90% reduction in attacks and perhaps even better if you get to those higher levels. So.

David Lebwohl: So what we would have, we think, is a one-time treatment that would prevent attacks potentially for the lifetime of the patient. Where this fits in, right now, people are getting prophylaxis either by injection or by pills. The injections work better in general than the pills, but many patients want to avoid them because of the discomfort, the inconvenience, etc.

What we would have we think is a onetime treatment that would prevent attacks potentially for the lifetime of the patient.

Where this fits in right now people are getting prophylaxis, either by injection or bye bye pills, the injections work better in general than the pills, but many patients want to avoid that because of the the just comfort and convenience et cetera.

Taking an injection. So we think that the both by getting excellent prophylaxis for patients and also being a one time treatment. That's avoids any issue, it's really a continuous reduction any issues of a recovery of levels that could occur with prophylaxis. This would become the preferred.

David Lebwohl: of taking an injection. So we think that both by getting excellent prophylaxis for patients and also being a one-time treatment that avoids any issues, it's really continuous reduction, any issues of recovery of levels that could occur with prophylaxis, this would become the preferred treatment for patients. The next question comes from Joseph Dorn with Cohen & Company. Please go ahead. Good morning, and thank you for taking my question.

<unk> for patients.

Thank you.

The next question comes from Joseph Thome with Cowen and company. Please go ahead.

Joseph Dorn: Just in terms of the easel update, will we be able to see some polyneuropathy functional symptom data at this time, or maybe when would you be in a position to provide this update? How long do you want to follow those patients out for? Thank you. David, when are we going to see some clinical data on polyneuropathy? Yes, so in the polyneuropathy arm, those measures come at later points in treatment, so it does take a long time to get them, and they are not yet available for easel.

Good morning, and thank you for taking my question just in terms of the easel update what we'd be able to see some polyneuropathy functional symptom data at this time or maybe when would you be in a position to provide this update how long do you want to follow those patients out for thank you.

David why don't we just couldn't see some clinical data polyneuropathy arm.

Yeah.

The Polyneuropathy arm those those measures comment later points in treatment.

So it does take a long time to get it and not yet available for evil. However, what we do know with the type of reductions we're seeing and then as mentioned 93% reduction this is better than what's been achieved with other agents and with that is also expected to potentially achieve.

Joseph Dorn: However, what we do know with the type of reductions we're seeing, and as mentioned, the 93% reduction, this is better than what's been achieved with other agents, and that is also expected to potentially achieve better clinical results for patients. If you look at data available from silencers, if you look at other types of amyloidosis, the lower the protein the patients have, the better their clinical outcome.

Other results clinical results for patients.

If you look at data available from from silence. There is if you look at other types of amyloidosis lowered the protein that patients have the better their clinical outcome. So that's so we won't have the clinical data to show, but we do depend on the results of other.

David Lebwohl: So we won't have the clinical data to show, but we do depend on the results of other studies to predict what will be happening with this type of effect. Great, thank you. The next question comes from Joon Lee with Truist Securities. Please go ahead. Hi, good morning, and congrats on the progress. This is May be on for June.

Studies to to predict what will be happening with this type of effect.

Great. Thank you.

The next question comes from Joon Lee with Truest Securities. Please go ahead.

Hi, good morning, and congrats on the progress this is Maggie on for June .

Joon Lee: So, our question, the first question is related to HAE. Ionis has, Donnie Dollarson, a 95% reduction in pre-calcarine and a 97% attack rate reduction after basically months 1, 5 to 17. So, the question would be, what is your goal for this treatment and how confident are you in reaching at least these levels or surpassing them? Thank you. Maybe I'll address that.

So our question.

The first question is related to the H E E.

I honest has oh.

Don't need all of a sudden now.

95% reduction in Calgary, and 97% attack a brief reduction out there basically.

One five to 17. So the question would be what is your goal for.

These treatment and how confident you are in.

Reaching.

If these levels or surpassing that thank you.

Well, maybe I'll address that thanks for the question.

John Leonard: Thanks for the question. The way we think about HAE and its treatment is that there are various elements that patients, doctors, and payers are going to want to address. Obviously, the first is the disease itself.

The way, we think about H E E and its treatment is that there's various elements that ah patients doctors and payers are going to want to address obviously the first as the disease itself and based on our preclinical data in extrapolating somewhat from the TR daily.

John Leonard: And based on our preclinical data and extrapolating somewhat from the PTR data we've accumulated so far, we're pretty confident that we'll be in a position to certainly meet and, we think, ultimately, perhaps surpass what's been achieved for virtually any treatment modality thus far, including, and I'm not sure those numbers are entirely representative of the two you just described, but including, you know, some of the more recent data. So, from an activity point of view, I think we're on the right track here.

We have accumulated so far.

We're pretty confident that we'll be in a position to it's certainly meets and.

We think ultimately perhaps surpass.

What's been achieved for virtually any treatment modality, thus far and including and I'm not sure. Those numbers are entirely representative that you just described but including.

Some of the more recent data.

John Leonard: Obviously, that needs to be confirmed in ongoing clinical trials, and we're all very interested in seeing attack rates as we accumulate additional back-up data in the ongoing study. And as I said earlier, you know, as that data accumulates, we'll certainly share it. But we also think that there are a couple of other elements that bedevil the treatment of these patients. Number one is the treatment burden. If you go and ask patients, if you ask doctors, one of the troublesome elements is what it takes to get to those effects. These are otherwise pretty normal people, you know, from a diseased point of view, and oftentimes they're young, including sometimes adolescents.

So I think from an activity point of view.

Where we're on the right track here, obviously that needs to be confirmed in ongoing clinical trials and we're all very interested in seeing attack rates as we accumulate additional knockdown data in the ongoing study and as I said earlier, you know set acute data accumulates, we'll certainly share it.

But we also think that there's a couple of other elements that.

But double.

The treatment of these patients number one is the treatment burden. If you don't ask patients. She if you ask doctors are one of the troublesome elements is what it takes to get to those effects. He said otherwise pretty normal people.

From a six point of view and oftentimes, they're young, including sometimes adolescence and so the number one issue once their attacks are.

John Leonard: And so, the number one issue, once their attacks are somewhat within control, is the treatment burden itself, and we believe that a one-and-done sort of potentially lifelong treatment will be a major advance for those patients, and that's certainly what the patients and the doctors tell us. But there's another element as well, which is the cost of these patients, and if you look certainly in the United States, for the most effective therapies, many of these patients have, just for access to the medicine alone, costs of over a million dollars, which is an extraordinary number over the lifetime of these patients, particularly when you think of the age of onset and when they're diagnosed.

Somewhat within control, it's treatment burden itself.

And we believe that a one and done sort of potentially lifelong treatment will be a major advance for those patients. So that's certainly what the patients and the doctors tell us.

But there's another element as well, which is the cost of these patients and if you look certainly in the United States.

For the most effective therapies.

Many of these patients have just for access to the medicine alone cost of over a million dollars a year, which is an extraordinary number over the lifetime of these patients, particularly when you think of the age of onset when they're diagnosed and so also from an economic point of view, we believe that there's a <unk>.

John Leonard: And so also from an economic point of view, we believe that there is a massive opportunity to improve the cost to these patients and to the health care system. So I think, all things considered, there will be attractive elements of this treatment for patients, payers, doctors, family members, caregivers, et cetera, and we expect that it'll be well received. I mean, when you think about this, and I think Salveen asked the question about the treatment paradigm, I don't think gene editing is going to be the very first intervention that doctors do.

Massive opportunity to improve on the cost to these patients and to the health care system. So I think all things considered.

Hum.

These will there will be attractive elements of this treatment for patients payers to doctors family members caregivers et cetera.

And yeah, we expect that it'll be well received I mean, when you think about this and I think celgene, who asked the question about the treatment paradigm I don't think gene editing is going to be the very first intervention that doctor Stuart I wouldnt recommend that as a physician, but certainly is as.

John Leonard: I wouldn't recommend that as a physician, but certainly, as information is accumulated and as we understand how this drug performs, I think it's going to be a very, very attractive offering for patients in the scheme of all the other elements that are available. That's very helpful.

Information is accumulated.

And as we understand how this drug performance I think it can be a very very attractive.

Offering for patients in.

In the scheme of all the other elements that are available.

That's very helpful. Thank you.

Sure.

John Leonard: Thank you. The next question comes from Devjit Chatterpadhyay with Guggenheim. Please go ahead. Hi, this is Ryan from DebJet.

The next question comes from W. P.

<unk> with Guggenheim. Please go ahead.

Devjit Chatterpadhyay: Just curious for 2002, what do you see as a good or great outcome for the interim data readout? And the second question for 3001, in some of our KOL discussions, the hypothesis was offered that insertion of wild-type AAT expression may result in suppression of PIZ through a negative feedback loop. Is there any precedent for this, and or has Intellia observed this phenomenon in preclinical studies?

Hi, This is Ryan on for Deb Jet just curious for 20 O. Two what do you see as a good or great outcome for the interim data readout and the second question for 30 year old one and some of our Kols discussions. The hypothesis was offered that insertion of wild type <unk>.

[noise] expression may result in suppression of P. I Z through a negative feedback loop is there any precedence for this <unk> has until he observed this phenomenon in preclinical studies.

John Leonard: Well, I'm going to turn to Laura with respect to 3001. But first, let me address 2002. And what do we think is a good data readout? You know, I think that 2002, sorry, the 2001 data is certainly setting our expectations in terms of the range of knockdowns. And, you know, all of these programs do have some differences, different patients, and how they perform, etc., so the guide itself is going to have some of its own idiosyncrasies. But we would expect to see knockdown levels that approximate where we are in the CTR program.

Well I'm going to turn to Lora with respect to 31, but first let me address 20 O two and what do we think it's a good data read out.

You know I think the 20th two I'm sorry, the 20th one.

Data is certainly setting our expectations in terms of the range of Knockdowns.

And you know all of these programs to have some differences different patients and how they perform et cetera.

John Leonard: But the most important readout is going to be attack rates. I mean, that's the final indicator of relating whatever editing one gets to what matters to the patient. And so that's going to be a story that shows where we are on a knockdown story.

And the guide itself is going to have some of its own idiosyncrasies, but we would expect to see.

<unk> knockdown levels that approximate where.

Where we've been in Ctr program, but the most important readout was gonna be attack rates I mean, that's the final.

Indicator of relating whatever editing one gets to what matters to the patient and so that's going to be a story that legs are where we are on a knockdown story, so I would say.

John Leonard: So I would say, you know, let's see how the data accumulates. As we've said, we'll share it later this year. And I would expect to see an interesting story develop that, as you know, we would want to advance as efficiently as possible. Laura, do you want to speak to 30.01 and what you think about the introduction of the transgene in patients with the underlying mutation? Yes, and, you know, briefly, right so, yes, there is the possibility that if you do have good expression of the, you know, the wild data allele, you may be able to restore the heterozygous phenotype in those livers, right?

Sales of data accumulates as we've said we'll share it's a later this year and.

I would expect to see.

An interesting story develop that as we would want to advance as efficiently as possible.

Laura do you want to speak to 31, and how you think about.

The introduction of the transgene.

And in patients with the underlying mutation.

Yes.

Yeah, So you're right. So yes, many be possibility that if you do have some good expansion.

No.

I you may be able to be started the simpler signage.

You've seen those neighbors right. So that's the number 115.

Laura Sepp Lorenzino: So that's, you know, one of the hypotheses we are pursuing with 30.01. The data will, you know, be shared when we're ready to share it, so stay tuned. Thanks for that.

We are pursuing we are experiencing.

Oh one.

The Baytown will you.

You know me sure. When you know were really Sharon I was thinking.

Yeah.

Thanks for that.

Gena Wang: The next question comes from Gena Wang with Barclays. Please go ahead. Thank you for taking my question. Just one regarding the 2002 HAE program. So when we look at the dose, you know, you jump from 0.3 milligram per kit to 0.9. Given your ATTR program of 0.7 milligram per kit, is that because you would like to achieve a higher level of knocking down? And I remember, John, you previously mentioned that 70% reduction would be sufficient to translate to clinical benefit. Was that the maximum knockdown level you wanted to achieve, or did you even want to do a beyond 70% reduction? Uh, well, thanks for the question, Gena. I mean, there are a couple of things.

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

Thank you for taking my question just one regarding that two O O to Itchy program. So when you look at that dose.

From that 0.3 milligram 2.9, keeping your HCR program of a 0.7 milligram per kit.

Is that because you would like to achieve higher level of knocking down.

And I remember that you previously mentioned, a 70% reduction would be sufficient to translate to clinical benefit was that the maximum knockdown level. You wanted to achieve all you want it even wanted to do I bet you on 70% reduction.

John Leonard: Remember.., first of all, while these are modular systems where the, The elements are essentially the same, going from PTR to HAE to Alpha-1 etc. Each individual guide will have its own characteristics with respect to potency. So we do need to establish, we can't just assume, we do need to establish a dose response, and that's exactly what we're doing so that we can see how these individual doses relate to the knockdown of calotrate which is the biomarker readout that we're using We extrapolate from those numbers, those knock-down numbers, to what we believe will be the expected clinical attack rate, and that comes from the work of others who have been establishing those relationships in advance of our work, but it relates to the questions that were asked before, you know, what's meaningful for patients, and what's really going to drive a profile of the drug that advances the ball, And we believe that this HAE may ultimately be a curable illness here, and that's certainly what we're striving for, and the expectation would be that deeper knock downs are likely to drive those sorts of outcomes.

Oh, well thanks for the question Gena I mean, it's a couple of things remember.

First of all well these are modular systems, where the you know the elements are essentially the same.

Going from <unk> to H E. Two alpha one et cetera.

Each of those individual guide will have its own characteristics with respect to potency. So we do need to establish.

We can't just assume we do need to establish a dose response curve and that's exactly what we're doing so that we can see how these individuals doses relate to the knockdown of of California, which is the biomarker readouts that we're using.

We extrapolate from those numbers the stock now.

The numbers to what we believe will be the expected clinical attack rate and that comes from the work of others, who have been establishing those relationships are in in advance for work, but it relates to the questions that were asked before.

[noise], what's meaningful for patients and what's really going to drive.

A profile of the drug that advances the ball for them.

And we believe that this may ultimately be a terrible illness here and that's certainly what we're striving for.

And the expectation would be that deeper knockdowns are likely to drive those sorts of outcomes. So we'll play out our phase one study in and look for that information. So that we can make the best judgment for the doses that we carry forward into what would be a registrational study.

John Leonard: So we'll play out our Phase One study and look for that information so that we can make the best judgment for the doses that we carry forward into what would be a registrational study. I wouldn't start by having a particular number from a dosing perspective in mind; it's really going to be what the readout is, and then we'll make the judgments as we go, which I think are the fundamentals of good drug development.

I wouldn't start by having a particular number from a dose dosing.

Prospected in mind, it's really going to be what's the read out and then we'll make the judgment as we go which I think are the fundamentals of good drug development.

John Leonard: John, like will be the knockdown also be a specific number you'll be looking for, like 70%, that you mentioned in the past? Will you be looking for like targeting that knockdown? We clearly want to have levels that go beyond 60%, and we've said that pretty much from the beginning, and that relates to what we see with TAX-0 and the good outcomes that they've had.

Junk like would be been knocked down also be specific number you would be looking for like 70% that you mentioned in the past would you be looking for like talking about that level.

We clearly want to have a.

Levels that go beyond 60% and we've said that.

John Leonard: So, for us, 60% would absolutely be a threshold in terms of how we think about the drug and the relationship of that biomarker to the clinical data. Thank you very much. The ultimate data, Gena, is going to be the clinical readout, and, you know, we will be testing levels of reduction that go well beyond 60% because that's where we believe you're going to get those really, really good clinical outcomes. Thank you. Sure. The next question comes from Luca Issi with RBC. Please go ahead.

Pretty much from the beginning and that relates to what we see.

With Tech zero.

And the good outcomes that they've had so for US 60% would absolutely be a threshold in terms of how we think about the drug at the relationship of that biomarker to the clinical data.

The ultimate data, though gena is gonna be the clinical readout, and we will be testing levels a reduction in that.

<unk>, you know go well beyond 60%.

Because that's where we believe you're going to get those really really.

Good clinical outcomes.

Thank you.

Sure.

The next question comes from Luca <unk> with RBC. Please go ahead.

Luca Issi: Well great, thanks so much for taking my question, congrats on all the progress. Maybe a quick one, the FDA recently issued guidance on gene editing, so wondering if you can comment on what your take on that document is, and maybe a bigger picture of how you're thinking about implications for filing your first IND. And I have a follow-up. As we read the guidance, it really conforms with how we think about how we run the programs.

Oh, great. Thanks, so much for taking my question congrats on the progress.

Maybe a quick one the SBA under the recently issued the guidance on gene editing. So wondering if you can comment on what was your take on that document and maybe bigger picture. How are you thinking about implications for filing your first A&D and I have a follow up.

As we read the guidance, it's really two forms with how we think about how we run the programs.

Luca Issi: We, you know, there are various elements in them. It's the preclinical work, it's the characterization of the on and off-target effects of the drug, and there's some, I'd say, very limited guidance that speaks to, you know, initial clinical programs because they tend to be, you know, each program is its own thing with its own particular considerations. Yeah, the fundamental point I think that the FDA made with respect to the clinical trial was, you know, just think about benefit risk, which is exactly where we start with all these programs. That was no real surprise to us.

We there's various elements in there it's the preclinical work, it's the characterization of the on and off target effects of the drug.

And there's some I would say very limited guidance that speaks to initial clinical programs because they tend to be.

Each program has its own thing with its own particular considerations.

The fundamental point I think the CFT made with respect to the clinical was just sneak about benefit risk, which is exactly where we start with all of its programs. So it was no real surprise to us.

John Leonard: Our view is that we've pretty much addressed most of the considerations that we saw in the guidance, so there really wasn't that much that added to the work that we're doing or changed how we think about it. And we're well into discussions with different regulatory agencies, including the FDA, that certainly address and exceed with respect to the specificity of the requirements of what's laid out in those guidance documents. By the way, I think the guidance is appropriate.

Hum.

Our view is is that.

We've pretty much addressed most.

Most of the considerations that we saw on the guide so there really wasn't that much that added to the work that we're doing or changed how we think about it.

And you know, we're well into discussions with different regulatory agencies, including the FDA.

That.

Certainly address and surpass with the respect to the specificity of the requirements of what's playing out in those guidance documents by the way I think the guidance is appropriate I think it's it's a good starting.

John Leonard: I think it's a good starting point for people coming into the space, and it's our interest as a company active in the space to have high standards, and one of the things that we feel very strongly about is the adequacy of off-target characterization, so we think the additional guidance from the FDA is welcome there. But, as you'll have seen in the publication we had back in the New England Journal, we think we've at least addressed any standards that have been laid out. Super helpful. And then, maybe quickly, what's the latest thinking on IP? I know CVC is obviously appealing, but how are you thinking about a potential sub-licensing agreement from the Broad should the decision be ultimately upheld?

Starting point for people coming into the space and it's it's our interest.

As the company active in this space to have high standards and one of the things that we feel very strongly about is the adequacy of off target characterization, which we think.

The additional guidance from the FDA says welcome there, but as you'll have seen in the public patiently head back in New England Journal, We think we've at.

At least addressed any standards that have been laid out.

Got it got it Super helpful. And then maybe quickly what's the latest thinking on IP I know CBC is obviously appealing, but how you're thinking about potential sub licensing agreement from the broad should a decision be ultimately upheld thanks, so much guys.

John Leonard: Thanks so much, guys. Sure. The process will play out. The findings thus far, you know, the process... All of the findings thus far have no bearing on how we decide or do what we do or what we choose to do. You know, it's full speed ahead with all the programs that we do. We've said since 2015, and I think now that none of these findings affect how we progress our programs.

Sure.

The process will play out.

The findings, thus far the processes and completes the finding thus far have no bearing on how we decide to do what we do or what we choose to do.

It's full speed ahead with all the progress that we do we've said.

Since 2015, I think now that you know none of these findings are affect how we progress our programs.

John Leonard: It's in everybody's interest, including the Broads, to work outside of, you know, a very, very limited area that this particular patent refers to if they want to progress their own work as well. So, I think at some point, there'll be, you know, if the legal process doesn't play out, I'm sure there's other ways to get to that. Thanks so much, guys, this comes from Steve Seedhouse of Raymond James. Hi, this is Timur Ivannikov on behalf of Steve.

And it's in everybody's interest, including the roads with respect to work outside of a very very limited area, but this particular patent refers to if they wanted to progress their own work as well so I think at some point therapy.

The legal process doesn't play it out I'm sure there's other ways to get to an agreement.

Got it thanks, so much guys.

The next question comes from Steve seat House of Raymond James. Please go ahead.

Hi, This is tomorrow, but it goes on for Steve.

Timur Ivannikov: So just a quick question for us in terms of the easel presentation. So you've mentioned presenting exposure details, and we didn't see any mention of a biopsy. Will you present liver biopsy data to maybe see the percent of edited cells to measure editing efficiency over time? No, because there are no biopsies to present.

A quick question for us in terms of the easel presentation. So you've mentioned are presenting exposed to details.

And we didn't see any mention of a biopsy will you present, a liver biopsy data to maybe see percent of itself too I'm not sure of editing efficiency over time.

John Leonard: We in investigators and regulators, for that matter, all agree that that's not a particularly informative analysis and probably subjects patients to more risk than any kind of benefit that one might get. I think Just about anybody who's looked at the space now believes that it's far more informative to do this on a preclinical basis where you can take healthy donor cells, these are primary hepatocytes, and subject them to many-fold higher levels of concentration, which we think is what defines an adequate probing of the off-target profile of these editing agents, and look with that provocative testing for any aspects of off-targets, and we' Okay, thank you very much. The next question comes from Mani Foroohar of SVP Securities. Please go ahead.

No because theres no biopsies to present, we and investigators and regulators for that matter all agree that that's not a particularly informative analysis and probably subject patients to more risk than any kind of benefit.

One might get.

I think.

Just about anybody who's looked at the space now believes that it's far more informative to do this on a preclinical basis, where you can take healthy donor cells as a primary hepatocytes and subject them to many fold higher levels of concentration, which we think is what defines an adequate.

Probing of the off target profile of these editing agents and look with that provocative testing for any aspects of off targets and we've done that and that's the work that was published in the New England Journal, a biopsy would provide far less information than that.

Okay. Thank you very much.

Sure.

The next question comes from money through her with SVP Securities. Please go ahead.

Mani Foroohar: Thanks for taking the question. Something a little more atmospheric and broad than some of the specific questions about individual programs that most of us call, obviously, there's, you know, we're going to start seeing with Alpha 1 antitrypsin, a little data from you guys talking along, you have some partnerships, looking at diseases of bone marrow, sickle cell specifically. Can you comment on what the timeline is that would be reasonable for us to start seeing data? Data is... What if I'm a human with an illness outside of the liver, and how should we think about delivering modalities as part of the modularity of your platform? So, do you consider lung disease of alpha-1-antripsin as a disease outside the liver, or are you considering that a liver-related disease?

Hey, Thanks for taking the question something a little more atmospheric and broad and some of the specific questions. There.

The individual programs that are in both of his call.

Obviously there were.

We're gonna seeing where alpha one antitrypsin a little data from Yahoo. Hagen, along some partnerships are looking at diseases of bone marrow sickle cell specifically can.

Can you comment on what the timeline is it reasonable for us to start seeing that.

Data and some human with an L. A with an illness outside of the liver, but how should we think about delivery modalities as part of the modularity of your platform.

So do you consider lung disease.

Alpha one antitrypsin is disease outside the litter liver or are you considering that a liver related disease. How do you think about that money.

Mani Foroohar: How do you think about that? I would primarily consider liver-related diseases since you're delivering your editing construct to hepatocytes. Yeah, okay, so I can't give guidance in terms of some of these other programs, but you know, there's a lot of interest and work going on within the company of moving beyond the liver. We've talked about some of the work that we've done in bone marrow-related diseases, specifically sickle cell. As that data matures and we have more to present at a preclinical level, we will share that, and then we can start thinking about what that means for the disease, you know, for development candidates and timelines, etc.

I would primarily consider liver disease sensor delivering.

They're delivering your rather than construct to a pad site.

Yeah, Okay. So.

I can't give guidance in terms of some of these other programs but.

There's a lot of interest and work going on within the company of moving beyond the liver we've talked about some of the work that we've done in bone marrow related diseases, specifically sickle cell.

There.

As that data matures and we have more to present, a preclinical level, we would share that and then we can start thinking about what that means for disease for a development candidates and timelines et cetera, but for.

Mani Foroohar: But for the, you know, immediate future here, I think we're going to be related to the programs we have in the clinic and, those are the ones that we've been talking about today. All right, thanks. Sure. Next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi, thanks for taking my question. So first on the easel presentation, in terms of durability.

For the you know.

Immediate future here I think we're gonna be related to the programs we have in the clinic.

And.

Those are the ones that we've been talking about today.

Alright. Thanks.

Sure.

The next question comes from young Zhou with Wells Fargo. Please go ahead.

Hi, Thanks for taking my questions. So.

So first on the easel presentation in terms of durability could we expect incremental three months additional durability for all of the patients compared with your March presentation.

Yanan Zhu: Do we expect incremental three months additional durability for all the patients compared with your mark? David, do you want to say a word about just, you know, what to expect at the EASL presentation? Yeah, so the same as you mentioned, we had mentioned before, right about two or 12 months follow-up.

David do you want to say a word about just you know what to expect that these will presentation.

David Lebwohl: And we will start to fill in cohorts here with more additional follow-up. So we think that'll be very valuable, that with the additional follow-up, we'll be able to talk about the number of patients who've reached important markers in their time. And we do think when we get there, that that data will speak for itself. So we really look forward to showing that soon. I think it's important to add, maybe, that as the study progresses, the data is accumulated, I think, David, in three monthly intervals.

Yeah. So the as you as you mentioned, we have mentioned before right about two with 12 month follow up and we will start to fill in cohorts here with with our more additional follow up. So we think that'll be very valuable that with the additional follow up we'll be able to talk about number of pace.

Once we have reached important markers and their time and we do think when we get there that that data will speak for itself. So we really look forward to showing that soon.

Well I think it's important to add maybe that as the study progresses.

Data is accumulated.

I think David and three monthly.

Uh huh.

David Lebwohl: And so while we have a lot of individual data points to present early in the observation phase, as these patients are followed for a longer period of time, it comes essentially in quarterly increments. And so going forward, that's the way I think about the And actually, it goes from 12 to 18 months, so there is a big gap from the 12 to 18 month point, just for people's expectations, but we'll make that very clear in the presentation when and what time. I got it.

[noise] intervals and so while we have a lot of individual data points percent early in the observation phase.

As these patients.

Followed for a longer period of time it comes essentially in quarterly increments.

Increments, so going forward, that's the way I think about this.

And actually it goes from 12 to 18 months. So there is a big gap from the 12 to 18 months point, just so people.

For expectations, but we'll make that very clear in the presentation when what's the time for my side.

David Lebwohl: That's very helpful. And then my other question is on 601. Thanks for your, you know, disclosure at the Keystone meeting, Adesola, over the weekend. With regard to your approach to knocking out receptionists, Edward Raycroft, both CD-8 and NK-Cell. Rejection from the host by CD8 or NK cells. This knocking out this receptor knocks down HLA-1 but does not eliminate HLA-1 in order to prevent NK rejection, and that's probably why you did not completely aim for the elimination of HLA-1. Because you didn't eliminate HLA-1, there is still some host CD8 activation, according to the preclinical data presented at Keystone. How should we think about how effective this approach will be? A Compared with...

Got it that's very helpful. And then my other question is on six O. One thanks for your disc.

Disclosure.

At the Keystone meeting.

Just this or last week.

Actually over the weekend so.

With regard to your approach of knocking out receptor X to address them, both CD eight and NK cell rejection from from the host to host a CD eight or NK cells I think.

That just knocking out this receptor knocks down H L. A one but does not eliminate a county one.

In order to.

To prevent NK rejection, that's probably why you did not completely aimed for complete elimination of each how a one.

But.

Because you didn't eliminate HLA one there is still some host C. D. Eight activation. According to the preclinical data presented at the Keystone How should we think about how effective it is approachable b a comparator with the H Mart.

Yanan Zhu: Conventional HLA-1 Now, Laura, do you want to contrast the approach we're taking with what we see others doing? You know, I just hasten to add, while Laura's on here, that we've not yet disclosed the precise edits that we make. But in that presentation, we showed, generally speaking, what were, you know, the characteristics that we're attempting to achieve. So Laura, do you just want to describe, you know, exactly what it is that we want in the attributes of these cells and why we're excited about 60 of them?

Conventional H H L. A y knockout approach. Thank you.

Laurent you want to contrasts.

The approach, we're taking with our what we see others doing.

Yeah.

Hasten to add well or it comes on here.

We've not disclosed yet the precise edits that we make but at that presentation. We showed generally speaking what were.

The characteristics that were attempting to achieve so largest you're just wanted describe you know exactly what you know.

What it is that we want in the attributes of these cells and why we're excited about 61.

Yanan Zhu: Yeah, and I'm sorry, but we're not yet describing exactly how we're doing it. But you know, there are three immunological problems that you need to overcome for allogeneic therapies that, you know, we believe we have addressed with our technology, right? So it's prevent graft versus host disease, then prevent rejection by CD4 and CD8 T cells. And you know, others are doing that, to some degree. The concern with other allogeneic therapies in development is that they do not prevent rejection by NK cells.

Yeah, and I'm, sorry, but we're not getting this kind of exactly how we're doing it but you know the theyre, the immunological and traveling and saying you know you need to account for allogeneic therapies that you know we believe we have addressed.

Our technology right. So it's B, then graft versus host T T than pre than rejection by T. Before in TBA pizza and others are doing that and to some degree the concern with you know either allogeneic therapy.

Element.

Is that and they do not prevent rejection by NK cells and these clinical data that Natalie.

Parking badly no short duration right.

Laura Sepp Lorenzino: And there's clinical data that now supports that with, you know, a short duration of effect, right? So what we've been able to do was to ensure that ourselves overcome all these three limitations, and they are not rejected by host NK cells. And at the same time, retain all the on target activity that we saw in the, you know, very efficient antitumor activity. The other thing to highlight here is that these cells are generated using our Intellia engineering process, where we do an M&B based, you know, engineering, sequential editing, and that allows us to have very high quality cells that are not exhausted, and that, you know, they can be manufactured with high quality attributes.

So what we've been able to do to ensure that our worst.

House overtime all of these three mutations and Theyre not rejected they host so and at the same time, we gain all the on target activity that we saw.

Yeah.

Very efficient antitumor activity and other thing to highlight here is that you know these carrington generated using our Italia engineering process, where we do.

And then B base and engineering sequentially any team and that allows us to have very high quality sounds bad Aeronautics homestead and bad debt.

Can be manufacturing high quality actually here.

John Leonard: Now, one thing to add to the work that Laura and her team have brought forward there is that we view this Allo approach as essentially a platform for the company, and 6.0.1 is the first example of our own wholly owned product moving forward, but it relates to the work we've done with Kyverna and Avancel where, as partners, we understand more about the shortcomings of what is the standard Allo approach out there. I think people are increasingly excited about this very differentiated approach and what we've been seeing what it can bring for patients, which is essentially, you know, off the shelf, the true ability to have something there immediately, but that's also going to persist beyond the, in our judgment, fairly poor performance of standard approaches where graphs tend to be vastly reduced in their whole number within three to four weeks or completely eliminated, and this, we think, solves that problem All right, thanks for the help. The last question will come from Jay Olson of Oppenheimer. Please go ahead.

Now one thing to add too.

The work that Laura and her team have brought forward. There is that we view this allo approach as essentially a platform for the company.

And [noise] 60, or what is the first example of our own wholly owned.

Product moving forward.

But it's relates to the work we've done with <unk> and even so where as partners understand more about the.

The shortcomings of what is the standard allo approach out there I think people I'm increasingly excited about this very differentiated approach and what we spend what it can bring for patient switches.

Essentially you know off the shelf the true [laughter], our ability to have something there immediately but that's also going to persist.

On the in our judgment fairly poor performance of standard approaches where grafts tend to be.

Vastly reduced and so number within three to four weeks or completely eliminated this week that solves that approach.

Or is that deficiency I should say.

Got it thanks for the color.

Last question, then will come from Jay Olson of Oppenheimer. Please go ahead.

Jay Olson: Well, hey, congratulations on the progress and thank you for the update. Since you have a large number of early stage clinical programs in your pipeline and preclinical programs, can you talk about how you're prioritizing all of those programs and also how you're optimizing your overall capital allocation? Thank you. Yeah, it's a really important question.

Oh, Hey, congrats on the progress and thank you for the update since you are a large number of early stage clinical programs in your pipeline and preclinical programs can you talk about how you're prioritizing all of those programs and also how your opt in optimizing your overall capital allocation. Thank you.

John Leonard: And I appreciate that you asked that. You know, we start by pursuing targets with modalities that we think are going to be highly differentiated and bring real, really important medical advances if they perform at the level that meets our expectations. And from the outset, we've wanted to generate a lot of optionality within the company and within our pipeline because we know that there's lots to learn. I mean, it's just a new platform, there's new approaches, etc, etc.

Yeah, It's a really important question and I appreciate that you asked it.

We start by pursuing targets and modalities that we think are going to be highly differentiated and bring real really important medical advances if they perform to the level that reaches our expectations.

From the outset, we've wanted to generate a lot of optionality within the company and within our pipeline because we've known that there's lots to learn I mean, it's just a new platform, just new approaches et cetera et cetera.

John Leonard: You'll see somewhat of a bias toward the In Vivo work. The results that we saw with the PTR program, we think broadly speak across the In Vivo pipeline, and that's something that we're very, very enthusiastic about, and the modular approach allows us to move that forward. On the Ex-Vivo side, we're doing it in a very stepwise fashion. What we try to do is isolate an important question, get what we think is a convincing answer, and then step forward as those programs play out.

You'll see somewhat of a bias to the in vivo work.

The.

Results that we saw with the TCR program, we think broadly speak across the in vivo pipeline and that's something that we're very very enthusiastic about the modular approach allows us to move that forward.

On the ex vivo side, we're doing it in a very stepwise fashion, we what we tried to do is isolate an important question.

[noise] to us as a convincing the answer and then stepped forward.

As those programs play out and right now I mean, we're very very interested in understanding how our approach to a T cell receptor performance because we think once we understand that with the platform. We've created we will open up space that gets outside the very narrow and extremely crowded largely diesel driven car.

John Leonard: And right now, I mean, we're very, very interested in understanding how our approach to a T-cell receptor performs because we think once we understand that with the platform we've created, we will open up space that gets outside the very narrow and extremely crowded, largely B-cell driven cartel. So that's one important question for us, and the other one is just showing that the Allo platform performs at a high level.

T space. So that's one important question first and the other one is just showing that the allo platform performed at.

At the high level.

John Leonard: And then you see from the collaborations that we're doing that we look to extend our reach by taking technology, aspects of work that we've done, perhaps even individual products, and working as appropriate to complement our reach. And together, we think that that's the best way forward. But we will, as with any pipeline, prune and make decisions as appropriate as we accumulate data and move forward in what we think is the best possible way to identify the most favorable attributes of any of the elements that we're working on.

Then.

You'll see from the collaborations that we're doing we look to extend our reach by taking technology aspects of work, we've done perhaps even individual products and work as appropriate to.

To complement our reach and together.

We think that that's the best way for it, but we will as with any pipeline crude and make decisions as appropriate as we accumulate data and move forward and what we think is the.

The best possible way to identify the most favorable attributes of any of the elements that we're working on.

Okay.

Ian Karp: This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks. Great. Thanks so much. And thanks, everyone, for joining us today and your continued interest and support in Intellia. And we certainly look forward to updating you on our progress in the future. Have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

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

Great. Thanks, so much and thanks, everyone for joining us today, and your continued interest and support and Italia and we certainly look forward to updating you on our progress in the future have a great day.

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

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