Q4 2021 Intellia Therapeutics Inc Earnings Call

Good morning, and welcome to the Intel yet therapeutics fourth quarter and full year 2021 financial results Conference call. My name is Andrew and I will be your conference operator today.

Andrew: Good morning, and welcome to the Intellia Therapeutics fourth quarter and full year 2021 financial results conference call. My name is Andrew, and I will be your conference operator today.

Andrew: Following formal remarks, we will open the call up for a question and answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press star then zero on your telephone keypad.

Following formal remarks, we will open the call up for.

A question and answer session.

This conference is being recorded at the company's request and will be available on the company's website. Following the end of the call.

As a reminder, all participants are currently in listen only mode.

If anyone requires operator assistance during the conference. Please press Star then zero on your telephone keypad.

I will now turn the conference over to Ian Karp.

Ian Karp: I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed. Thank you all. Good morning, everyone.

Senior Vice President of Investor Relations and corporate communications at Intel Leah. Please proceed.

Thank you operator.

Ian Karp: Welcome to Intellia Therapeutics fourth quarter and full year 2021 earnings, 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 & Media section of Intellia's website at intelliatx.com, This call is being broadcast live and a replay will be archived on the company's, At this time, I would like to take a minute to remind listeners that during the call, Intellia Management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for 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.

Good morning, everyone welcome to <unk> Therapeutics fourth quarter and full year 2021 earnings call.

Earlier. This morning until 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 <unk> Dot com.

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

At this time I would like to take a minute to remind listeners that during the call and tell the 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 until he undertakes no duty.

To update this information unless required by law.

Joining me from Intel you are Dr. John Leonard Chief Executive Officer.

Ian Karp: Joining me from Intellia are Dr. John Leonard, Chief Executive, and Glenn Goddard, Chief Financial. Dr. David Lebwohl, Chief Medical Officer, and Dr. Laura Sepp Lorenzino, Chief Scientific Officer, will also be available for the Q&A portion. John will begin with an overview of recent business highlights.

And Glenn Goddard Chief Financial Officer.

Dr. David Loeb Wall, Chief Medical Officer, and Doctor, Laura step learn Dino Chief Scientific Officer will also be available for the Q&A portion of today's call.

John will begin with an overview of recent business highlights.

Hi, Glenn who will review <unk> financial results for the fourth quarter and full year 2021.

John will provide concluding remarks, and then we will open up the call for Q&A with that I'll turn the call over to John .

John Leonard: Followed by Glenn, who will review Intellia's financial results for the fourth quarter and full year 2019. John will provide concluding remarks and then we will open up the call for.., with that I'll turn the call over to, Thank you, Ian, and thank you all for joining us this morning. At Intellia, we're building a full-spectrum genome editing company with the industry's broadest and deepest toolbox to fully realize the promise of CRISPR-based medicines for both in vivo and ex vivo applications.

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

And until you were building a full spectrum genome editing company with the industry's broadest and deepest toolbox fully realize the promise of CRISPR based medicines for both in vivo and ex vivo applications.

John Leonard: 2021 was a landmark year for, during which we shared the first clinical data offering proof of concept for our platform, and showing it is possible to precisely edit a disease-causing gene within the body through a systemically-delivered CRISPR-based therapy. We initiated two additional clinical programs, dosing the first patient with NTLA-2002 and screening AML patients for NTLA-5001's first in human study. We nominated two new development candidates leveraging our targeted insertion platform. NTLA 3001 for alpha 1 antitrypsin deficiency and a program for hemophilia B led by our partner Regeneron.

21 was a landmark year for until you bring which we shared the first clinical data offering proof of concept for our platform and showing it is possible to precisely edit a disease, causing gene within the body through a systemically delivered CRISPR based therapy.

We initiated two additional clinical programs dosing the first patient with until late 'twenty, two and screening AML patients for until they feel ones first in human study.

We nominated two new development candidates leveraging our targeted insertion platform until a 30 year old one for Alpha one antitrypsin deficiency and a program for hemophilia B led by our partner Regeneron.

We also presented several noteworthy platform advancements, including preclinical proof of concept for in vivo editing of bone marrow and novel Allogeneic technology to engineer ourselves capable of ebay immune attack.

John Leonard: We also presented several noteworthy platform advancements, including preclinical proof of concept for in vivo editing of bone marrow. A novel, Elegineg, technology, co-engineer, sales, capable of rebating a unit pack, and a proprietary base setter, and finally, we launched a new company called Evans. We launched a new company called Evans, and we launched a new company called Evans, in partnership with Sulix and Blackstone, to develop allogeneic universal CAR T cell therapy. This collaboration is another example of our strategy to maximize the value of our platform and gain future product rights to innovative therapy. Well, we accomplished a tremendous amount in 2021.

And our proprietary based Saturday.

And finally, we launched a new company called avid so in partnership with <unk> and Blackstone to develop allogeneic Universal car T cell therapies. This collaboration is another example of our strategy to maximize the value of our platform and gain future product rights to innovative therapies.

While we accomplished a tremendous amount in 2021, we are already building. Upon these achievements in 2022 more specifically this year, we're focused on three core priorities first accelerating the clinical validation of our in vivo pipeline.

John Leonard: We are already building upon these achievements in 2022. More specifically, this year, we're focused on three core priorities. First, accelerating the clinical validation of our in vivo pipeline. On this front, we're looking forward to presenting additional clinical data from our lead candidate, NTLA 2001 for ATTR-MOLOBIOSUS next week. And later this year, we plan to present initial clinical data from NTLA-2002 for the HAE program.

On this front, we're looking forward to presenting additional clinical data from our lead candidates and kill a 'twenty one for <unk> Amyloidosis next week.

And later this year, we plan to present initial clinical data until late 'twenty two for the H M E program.

John Leonard: Next, we are actively expanding our pipeline by advancing NTLA 5001, our first wholly owned ex vivo candidate to enter the clinic, along with the nomination of multiple new development candidates in both the in vivo and ex vivo settings, as well as through strategic business development opportunities. And finally, we're building on our scientific leadership by driving forward key platform innovation through the expansion of our genome editing, delivery, and cell engineering capabilities. With robust execution against these objectives so far in 2022, Intellia is firing on all cylinders. Our Phase 1 study of MTLA-2001, recently expanded to include an additional arm with cardiomyopathy patients, continues to progress.

Next we are actively expanding our pipeline advancing until a 50 year old one our first wholly owned ex vivo candidate enter the clinic along with the nomination of multiple new development candidates in both the in vivo index people settings, as well as through strategic business development opportunities and fine.

We're building on our scientific leadership by driving forward key platform innovation through expansion of our genome editing delivery and cell engineering capabilities.

With robust execution against these objectives, so far in 2022, and Kelly is firing on all cylinders.

Our phase one study of until late 20th one recently expanded to include an additional arm with cardiomyopathy patients continues to progress well.

John Leonard: We look forward to hosting a company sponsored event next week, bring which we plan to present additional interim data, from patients with hereditary ATTR and Loydosis, with Pauli Neuro- The event will feature data from all four dose cohorts in Part 1, the Single Ascending Dose, It will include safety and serum GTR reduction data, as well as an early look at durability across all cohorts. We expect these results to inform the dose selection for part two, and we remain on track to initiate the single dose expansion cohort in the first quarter of this year. For MGLA-2002, we continue to dose patients in the dose escalation portion of the Phase 1-2 study.

Look forward to hosting our company sponsored event next week, bringing which we plan to present additional interim data from patients with hereditary <unk> amyloidosis with.

Polyneuropathy.

Well featured data from all four dose cohorts in part one the single ascending dose portion. It will include safety and serum TGI reduction data as well as an early look at durability across all cohorts. We expect these results to inform the dose selection for part two and we remain on track to initiate the single.

Dose expansion cohort in the first quarter of this year.

<unk> 20th too we continue to dose patients in the dose escalation portion of the phase one two study.

John Leonard: Based on the insights gained from NTLA-2001, which are directly applicable to NTLA-2002, we believe we've increased the likelihood of success as we advance this program. Looking ahead, we anticipate presenting the first cut of interim data from this trial for the second half of this year. In addition to NTLA-2002, we are now advancing two wholly-owned development candidates for the treatment of Alpha-1 Antitrypsin Deficiency, or AATD. This includes NTLA 3001, a gene insertion candidate for AATD-associated lung disease, for which we expect to file an INV or equivalent application next year.

Based on the insights gained from until late 'twenty, one which are directly applicable until late 'twenty. Two we believe we have increased the likelihood of success as we advance this program looking.

Looking ahead, we anticipate presenting the first cut of the interim data from this trial in second half of this year.

In addition, 10 till late 'twenty two we're now advancing two wholly owned development candidates for the treatment of Alpha one antitrypsin deficiency or a T D.

This includes until a 30 L. One gene insertion candidate for a P. D associated lung disease for which we expect to file in INV or equivalent application next year and today. We're pleased to announce the nomination of insulate 20, Oh suite, a knockout candidate for the liver manifestations.

John Leonard: And today, we're pleased to announce the nomination of NTLA 2003, a knockout candidate for the liver manifestation of AATD. NTLA 2003 is designed to inactivate the Serpin A1 gene responsible for the production of abnormal alpha-1 protein in the liver, with the aim of halting the progression of liver disease and eliminating the need for liver transplant. For AATD, our modular platform provides us the optionality for patient-tailored treatments relevant to the particular disease manifestation. Moving on to our Ex Viva pipe.

Station of a a T D until late 'twenty three is designed to inactivate the surpassing a one gene responsible for the production of abnormal one protein in the liver with the aim of halting the progression of liver disease and eliminating the need for liver transplant.

A T D. Our modular platform provides us the optionality for patient tailored treatments relevant to the particular disease manifestation.

Moving onto our ex vivo pipeline Carinthia like 50 on one we've begun enrolling patients in the phase <unk> study and expect to dose the first AML patient.

John Leonard: For NTLA 50-01, we've begun enrolling patients in the Phase I-IIa study and expect to dose the first AML patient with our autologous TCR T-cell therapy in the coming weeks. Today, we are also excited to announce the nomination of our first Allogeneic Development Candidate, NTLA-6001. NTLA 6001 is an aloe CAR T designed for the treatment of CD30 positive expressing hematologic cancer, such as relapsed or refractory classical Hodgkin's lymphoma. It was developed using our proprietary Allogeneic Cell Engineering platform. In preclinical studies, our allogeneic T cells were shielded from immune rejection by both host T cell and, critically important, host NK cell attack.

Paula gifts TCR T cell therapy in the coming weeks.

We are also excited to announce the nomination of our first allogeneic development candidate and P. L. A 60 watt and feel like 60, or one is an allo car T. Designed for the treatment of CD 30 positive expressing hematologic cancers, such as relapsed or refractory classical Hodgkin's lymphoma.

It was developed using our proprietary allogeneic cell engineering platform.

In preclinical studies or allogeneic T cells were shielded from immune rejection by both host T cell and critically important host NK cell attack.

John Leonard: This approach is distinct from others and is designed to ensure long-term persistence of the engineered cells. We are currently advancing this program towards IMD-enabling activities and plan to present preclinical data leading to the development of MTLA6801 at an upcoming scientific conference this year. In parallel, we continue to drive forward our platform innovation, maintaining our leadership position at the forefront of the genome editing revolution. Reflective of this strategy, we announced in February the acquisition of Rewrite Therapeutics, a private biotechnology company whose DNA writing technology may enable a range of additional editing strategies.

This approach is distinct from others and is designed to ensure long term persistence of the engineered cells. We're currently advancing this program towards IND, enabling activities and plan to present preclinical data leading to the development of MTL, a 60 or one at an upcoming scientific conference this year.

In parallel we continue to drive forward our platform innovation, maintaining our leadership position at the forefront of the genome editing where evolution.

Reflective of this strategy, we announced in February the acquisition of rewrite Therapeutics, a private biotechnology company, whose DNA writing technology may enable a range of additional editing strategies. The acquisition of rewrite further expands our leading genome editing tool box.

John Leonard: The acquisition of re-write further expands our leading genome editing toolbox by adding complementary technologies to our existing CRISPR-CAST-9 and face editing capabilities, thereby allowing us to employ the best tool for each therapeutic application, With the strength and breadth of our CRISPR-based platform, we recognize that our proprietary technologies can have expanded application when we strategically partner with others who possess complementary capabilities. This year, we've already completed two strategic collaborations, both of which extend the reach of our platform beyond our core areas of focus and provide us with valuable commercial product rights to future programs.

Adding complementary technologies to our existing CRISPR, Cas nine and base editing capabilities, thereby allowing us to employ the best tool for each therapeutic application.

With the strength and breadth of our CRISPR based platform, we recognize that our proprietary technologies can have expanded application when we strategically partner with others, who possess complementary capabilities.

This year, we've already completed two strategic collaborations both of which extend the reach of our platform beyond our core areas of focus and provide us with valuable commercial product rights to future programs.

In January we announced a collaboration agreement with Kyprolis therapeutics to leverage our allogeneic platform to develop K Y D 201, and Allo CD 19 car T cell investigational candidate for the treatment of select autoimmune diseases.

John Leonard: In January, we announced a collaboration agreement with Kyberna Therapeutics to leverage our allogeneic platform to develop KYB201, an LLCD19 CAR T cell investigational candidate for the treatment of select autoimmune disease, This is a novel approach aimed at targeting CD19 for inflammatory diseases as compared to traditional oncology in that case.

This is a novel approach aimed at targeting CD 19 for inflammatory diseases as compared to traditional oncology medications importantly, with an option to lead U S. Commercialization for this candidate under our co development and co commercialization agreement.

John Leonard: Importantly, we have an option to lead U.S. commercialization for this candidate under a co-development and co-commercialization agreement. And just this month, we announced a collaboration agreement with Owen K, to develop CRISPR edited NK cell therapies for the treatment of cancer. NK cells are specialized, naturally occurring immune cells that play a critical role in immune activation against abnormal cells, including cancer cells.

And just this month, we announced a collaboration agreement with Owens taste therapeutics to develop CRISPR edited NK cell therapies for the treatment of cancer.

T cells are specialized naturally occurring immune cells that play a critical role in immune activation against abnormal cells, including cancer cells.

John Leonard: The agreement grants O&K a non-exclusive license to our proprietary ex vivo genome editing platform for up to five in case cell therapy. Similar to the Kiberna transaction, we hold rights to global co-development and co-commercialization options, including lead U.S. commercialization rights for up to two engineered cell therapies derived from the collaboration. Finally, earlier this week, we announced a lease agreement to develop a 140,000 square foot facility in Walden, Massachusetts, to support the manufacturing of key components for our CRISPR based medicine. This new facility will be GMP compliant and offer capacity and capabilities to deliver preclinical through commercial supply for our rapidly expanding pipeline.

Agreement grants <unk>, a nonexclusive license to our proprietary ex vivo genome editing platform for up to five and case cell therapies.

Similar to like Hibernia transaction, we hold rights to global co development and co commercialization options, including lead U S commercialization rights for up to two engineered cell therapies derived from collaboration.

Finally earlier this week, we announced a lease agreement to develop a 140000 square foot facility in Waltham, Massachusetts to support the manufacturing of key components for our CRISPR based medicines.

This new facility will be GMP compliant and offer capacity and capabilities to deliver preclinical through commercial supply for our rapidly expanding pipeline.

Glenn Goddard: The ability to efficiently and reliably manufacture our products is crucial to ensuring commercial readiness and, ultimately, for a mission to bring transformational medicines to pay for, All together with these recent announcements, we've carried forward the strong momentum of the past positioning Intellia to advance the next wave of clinical candidates while ensuring we stay at the cutting edge for years to come. With that, I'll now hand over the call to Glenn, our CFO, who will provide an overview of our fourth quarter and full year 2021 financial results.

The ability to efficiently and reliably manufacture our products is crucial to ensuring commercial readiness and ultimately permission to bring transformational medicines to patients altogether with these recent announcements we've carried forward the strong momentum of the past year positioning and Telia to advance the next wave of clinical care.

Candidates, while ensuring we stay at the cutting edge for years to come.

With that I'll now hand over the call to Glenn our CFO , who will provide an overview of our fourth quarter and full year 2021 financial results.

Thank you John and good morning, everyone and tell you is in a strong financial position as we aggressively advance and expand our pipeline.

Glenn Goddard: Thank you, John. And good morning, everyone. Intellia is in a strong financial position as we aggressively advance and expand our pipeline. Cash, Cash Equivalence, and Marketless Securities, or $1.1 billion as of December 31, 2021, appeared to $597.4 million as of December 31, 2020. The increase was mainly driven by net proceeds of $648.3 million from our July follow-on offering. 45.3 million dollars of net proceeds from the company's ATM agreement. 45.3 million dollars of net proceeds from the company's ATM agreement. $43.1 million in proceeds from an employee-based stock plan, and $6.3 million from Regeneron Cost Share. These increases were offset in part by cash used to fund operations.

Our cash cash equivalents in marketable securities or $1 $1 billion as of December 31, 2021, compared to $597 $4 million as of December 31, 2020.

The increase was mainly driven by net proceeds of $648 $3 million from our July follow on offering.

$45 $3 million of net proceeds from the company's ATM agreement.

$43 $1 million and proceeds from employee based stock plans.

In $6 $3 million from Regeneron cost sharing.

These increases were offset in part by cash used to fund operations of $254 $7 million.

Glenn Goddard: $254.7 million. Our collaboration revenue increased by $6.3 million to $12.9 million during the fourth quarter of 2021, compared to $6.6 million during the fourth quarter of 2020. This increase was driven by $5.8 million in revenue recorded in 2021 from our joint venture with Avancel. Our R&D expenses increased by $32.9 million to $71.2 million during the fourth quarter of 2021, compared to $38.2 million during the fourth quarter of 2020. This increase was mainly driven by the advancement of our LEAD programs and the expansion of the R&D organization to support these programs.

Our collaboration revenue increased by $6 $3 million to $12 $9 million during the fourth quarter of 2021 compared to $6 $6 million during the fourth quarter of 2020.

This increase was driven by $5 $8 million in revenue recorded in 2021 from our joint venture with have himself.

Our R&D expenses increased by $32 $9 million to $71 $2 million during the fourth quarter of 2021 compared to $38 $2 million during the fourth quarter of 2020.

This increase was mainly driven by the advancement of our lead programs and the expansion of the R&D organization to support these programs.

Our G&A expenses increased by $11 $3 million to $22 $1 million during the fourth quarter of 2021 compared to $10 $8 million during the fourth quarter of 2020.

Glenn Goddard: Our G&A expenses increased by $11.3 million to $22.1 million during the fourth quarter of 2021, compared to $10.8 million during the fourth quarter of 2020. This increase was mainly related to employee related expenses including stock-based compensation of $3.8 million. This increase was mainly related to employee related expenses including stock-based compensation of $3.8 million.

This increase was mainly related to employee related expenses, including stock based compensation of $3 $8 million.

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

John Leonard: Finally, we expect our current cash balance to fund our operating plans beyond the next 24 months, as Intellia is well positioned to drive long-term growth. With that, I will now turn the call back over to John for closing remarks. Thank you, Glenn.

I can tell you is well positioned to drive long term growth.

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

Thank you Glenn.

John Leonard: We are already well on our way towards executing against our strategic priorities across all facets of the business. We're advancing robust pipeline, including both holy owned and partnered programs, now with eight development candidates, four of which are in the clinic. We're delivering against our corporate objectives and rapidly expanding the reach of our platform to accelerate the impact on patients. We're expanding our manufacturing network by adding in-house GMP manufacturing capacity to support our continued growth.

We are already well on our way towards executing against our strategic priorities across all facets of the business, we're advancing a robust pipeline, including both wholly owned and partnered programs now with eight development candidates four of which are in the clinic, we're delivering against our corporate objectives and rapidly expanding the reach of our.

Our platform to accelerate the impact on patients, we're expanding our manufacturing network by adding in house GMP manufacturing capacity to support our continued growth and will continue to propel our own scientific leadership and innovation to support the next wave of clinical candidates.

John Leonard: And we've continued to propel our own scientific leadership and innovation to support the next wave of clinical candidates. Despite all this progress... We still have much to accomplish later in the year. Before we open the call, the question... We understand many of you are interested in the upcoming NTLA-2001 investor event. Given our proximity to the data readout, we will not be addressing any questions regarding our progress with NTLA-2001 or the planned interim data on this call.

Despite all of this progress we still have much to accomplish later in the year before.

Before we open the call to questions. We understand many of you are interested in the upcoming into late 'twenty, one one industry that given our proximity to the data readout, we will not be addressing any questions regarding our progress with until a 'twenty one or the planned interim data on this call. We look forward to sharing additional data with you next week.

John Leonard: We look forward to sharing additional data with you next week and kindly request that you refrain from using today's call to ask questions on this topic. With that, we'd be happy to answer any questions about the rest of our pipeline and platform. Operator. We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys.

And kindly request that you refrain from using today's call to ask questions on this topic with that we'd be happy to answer any questions about the rest of our pipeline and platform.

Operator.

We will now begin the question and answer session.

To ask a question you May press Star then one on your Touchtone phone. If you were using a speakerphone. Please pick up your handset before pressing the keys to withdraw your question. Please press Star then two.

Andrew: 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 Joon Lee with Truist. Please go ahead.

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

The first question comes from John .

Excuse me June Lee with Truest. Please go ahead.

Hi, Thanks for taking our questions after the updates and looking forward to the data next next week.

Joon Lee: Hi, thanks for taking our questions and for the updates and looking forward to the data next week. On the other pipeline program, can you elaborate on the strategy for 2003 and 3.0.1? I mean, why not combine these as a single therapy program?

On the other pipeline program can you elaborate on the strategy for 2002 or three and three O. One I mean, why not combine DS as a single therapy program.

John Leonard: And also, how do you plan to screen patients for these two programs? And I have a quick follow-up. Thanks, June.

And also how do you plan to screen patients for these two programs and then I have a quick follow up after that.

Thanks, John good to hear from you.

John Leonard: Good to hear from you. At this point, we view the programs as independent, uh... but that doesn't mean that there's not a point where you know they could come together in a single patient uh... proceeding the way we're doing it it gives us we think, Maximal flexibility, and as I'm sure you know, there's different disease manifestations that may tip the balance more in favor of one intervention for a type of patient and the other intervention for another type of patient.

This point, we view the programs.

Independents.

But that doesn't mean that there's not a point where they can come together in a single patient.

The.

Preceding the way we're doing it it gives us we think Max.

John Leonard: So at this point, we like to keep it simple. And we think that that's in the best interest of advancing the programs most quickly. I'm not sure I understood your question about screening patients, if maybe you could elaborate on that a little bit. Sure. I mean, do Alpha-1 Antitrypsin deficient patients manifest lung and liver disease separately? Isn't it driven by the same mutations? Deepak Chopra and Joseph Deang, etiology for either manifestation is the same gene and you know it's important to bear in mind the nature of the problem however plays out differently in different organs so in the case of liver and you know liver disease and patients can certainly have liver disease without lung manifestations, It's a local problem where the average protein doesn't get out of the liver appropriately and causes local inflammation whereas most of the pathology occurs and this is typically later in life in the long when that protein that didn't get out is needed to prevent the development of infecium in the long.

Maximum flexibility as I'm sure you know it's different disease manifestations that.

Tipped the balance more in paper one intervention for types of patients to meet the other than the potential for another type of patients. So at this point, we'd like to keep it simple.

We think that that's in the best interest in advancing the programs most quickly.

I'm not sure I understood your question about screening patients.

If maybe you could elaborate on that a little bit for me.

Sure.

I mean do do alpha one antitrypsin deficiency patients manifest lung and liver disease separately. It isn't it driven by the same mutation such that they.

Both have both matters.

Patients should benefit.

Yeah, No no I understand I understand so that's helpful.

The you're correct in that the underlying.

Etiology for either manifestation is the same cheat and.

It's important to bear in mind.

The nature of the problem. However, it plays out differently in different Oregon, So in the case of liver.

And you know liver disease in patients that certainly have liver disease without lung manifestations.

John Leonard: And that case, what you want to do is focus on replacement therapy. So patients frequently figure later on. In the future life, we'll have primarily the pulmonary manifesto. And oftentimes, early in life, a small proportion of patients with the underlying gene problem will have primarily a liver manifestation, can be a mixed phenotype as time goes on, but typically it's predominantly one or the other.

It's a local problem, where P. Aberrant protein doesn't get out of the liver appropriately cautious local information, whereas most of the pathology occurs and this is typically lighter life in the lung when that protein that didn't get out is needed to prove.

Hence the.

Development of its emphysema lung in that case, what you want to do is focus on replacement therapy.

So patients are frequently particular later life will have primarily the pulmonary manifestations and oftentimes early in life, a small proportion of patients with underlying gene problem will have primarily liver manifestation.

Can be a mixed phenotype is as time goes on but typically it's predominantly one or the other and so in this case, we're able to.

John Leonard: And so in this case, we're able to, you know, tailor the therapy for the particular manifestation. But again, that does not mean. In any way that we can't bring them together in the same patient, remember that what we're doing is knocking out the particular disease-causing gene with 2003, and the insertion program targets a different gene for its expression, which is the albumin locus. And so you can have both of these interventions residing in the same patient, but they can get there at different times. So again, we think this keeps it simple for us, at least at the beginning here, and gives us a good chance to learn as we go in tailored therapy. Got it.

Taylor the therapy for the particular manifestation, but again that does not mean.

And any way that we can't bring them together in the same patient remember that what we're doing is knocking out a particular disease, causing genes.

23, and the insertion program targets are different.

Gene for especially the albumin locus and so you can have both of these interventions for zions St patient.

But they can get to a different time so again.

We think this keeps it simple for all suddenly stopped the beginning here and it gives us a good chance to learn as we go and tailor therapy.

John Leonard: And a quick follow up, you know, you recently announced acquisition of BeRight for $45 million. And it seems like based on the founders, they have a tool that allows them to find more tools. Is this something what did you see there that attracted you to the deal?

Got it and then a quick follow up you recently announced the acquisition of be right for $45 million and it seems like based on the founders they have a tool that allows them to find more tools.

Is this something but did you see there that attracted you to the deal.

John Leonard: Is that something that would allow you to do next generation things like combine 2003 and 2001 in a single step? eventually. Thank you. Yeah, thanks. Well, Rewrite is part of our overarching strategy. So when we say we want to be a full spectrum and consider ourselves a full spectrum genome editing company, that means really three legs to the stool, you know, the in vivo programs in the clinic, the ex vivo programs in the clinic.

Is that something that would allow you to do next generation things like combined 2003, and 2000 2001 in a single step.

John Leonard: But critically important is that third leg of having a platform with which essentially is a toolbox of all kinds of different modalities, I think it's a mistake to think that any one particular genome editing approach is going to be definitive and address all particular targets that one might want to pursue, and so we spend a lot of time and invest a lot of effort in building a toolbox that has all kinds of different editing modalities. It's also true we spend a lot of time thinking about delivery modalities.

Thank you.

Yeah, Thanks, well rewrite as part of our overarching strategy. So when we say we want to be a full spectrum and consider ourselves as a full spectrum genome editing company that means real.

Really three legs to the stool the in vivo programs in the clinic the ex vivo programs in the clinic, but critically important is that third leg of having a platform with which essentially was a toolbox.

Of all kinds of different modalities I.

I think it's a mistake to think that any one particular genome editing approach is going to be definitive in that dress all.

Particular targets.

<unk> targets, the one might want to pursue and so we spent a lot of time and invest a lot of effort in building a toolbox that has all kinds of different editing without.

John Leonard: So, you know, that toolbox is full of things that we think is going to really open up opportunities beyond where we already are as we go forward. So, in the case of rewrites, there's interesting technology there that permits us to do a form of gene writing. You know, there's the canonical CRISPR, which we know is so powerful, and we've, you know, been presenting data that we've generated with that. There's particular instances where one might want to use a base setter.

It's also true we spent a lot of time thinking about delivery modalities. So that tool boxes is full of things that we think it's going to really open up opportunities beyond where we already are as we go forward. So in the case of rewrites.

There's.

Interesting technology, there that permits us to do a form of gene writing.

You know, there's the canonical Christopher which we know is so powerful.

Presenting data that we've generated with that there's particular instances, where one might want to use a base center. We think that's ideally suited for multiplex knockouts in the ex vivo setting.

John Leonard: We think that's ideally suited for multiplex knockouts in the ex vivo setting. And then there's gene writing, where one can introduce sequences of varying lengths, including sequences as short as a single nucleotide. That technology, I think, is immature at this time, but with some of the capabilities that we have and the insights that we've built over the years, we think that we'll be able to mature it and bring it forward to add to the sorts of genetic problems that we can address.

And then there's gene writing, where one can introduce sequences.

Varying lengths, including sequences as short as a single nucleotide.

That technology I think is immature at this time, but with some of the capabilities, we have and the insights that we've built over the years, we think that we'll be able to mature it and bring it forward to add to the sorts of genetic problems that we can address them as we make progress on that you know we will.

John Leonard: As we make progress on that, we will present data at the appropriate scientific and medical forums so you get a sense of where we are and where we think that that tool is serving as well. But again, just view this as another, one more implement that we have that let's just keep broadening our scope. Thank you so much.

<unk> data at the appropriate scientific and medical forums. So you get a sense of where we are and where we think that that too.

Tool is serving as well, but again just view this as another on one more implement that we have that lets just keep broadening our scope.

Thank you so much.

Sure.

Maury Raycroft: Sure. The next question comes from Maury Raycroft with Jeffreys. Please go ahead.

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

Hi, good morning, everyone and thanks for taking my questions acknowledging that you're not commenting on GTR, probably neuropathy today can you elaborate on how many achy Chiara cardiomyopathy patients had been dosed at this point and if we can expect an update this year from this cohort.

John Leonard: Hi, good morning everyone and thanks for taking my questions. Acknowledging that you're not commenting on ATTR polyneuropathy today, can you elaborate on how many ATTR cardiomyopathy patients have been dosed at this point and if we can expect an update this year from this cohort? Good morning, Maury.

Good morning, Marty I appreciate your persistence.

Maury Raycroft: I appreciate your persistence, but that falls into the broader rubric, let's say, of 2001, and we'll be happy to talk about a lot of that stuff when we come together on Monday, and we'll devote the session to talking about the 2001 program at large. So, hope to see you there. Got it.

But that falls into the broader.

Rubric, let's say of 20 O one and we'll be happy to talk about a lot of that stuff will come together on a Monday and well, we'll devote secession two talking about.

21, a program writ large so.

Hope to see you there.

John Leonard: We'll definitely be there. And I guess another question for HAE, I'm just wondering if you can talk a little bit more about what to expect for that update second half of this year. Could we expect to see data from all three dose cohorts? I think it's premature to say how much data we'll have. The goal is to share some data in the second half of this year. And you should anticipate that we'll think about it very, very similarly to what we did with, you know, last June with 2001. We apply the same principles of having information that's consistent, meaningful, interpretable, and that guides us.

Got it will definitely be there and I guess, there's a another question for H E. E. I'm just wondering if you could talk a little bit more about what to expect for that update a second half of this year or could we expect to see data from all three dose cohorts.

I think it's premature to say how much data, we'll have our goal is to share.

Some data in the second half of this year and you should anticipate that we will think about it very very similar to what we did with.

Last June with 20 O one.

We apply the same principles of having information that's consistent meaningful interpretable in that guide says, but we're making good progress. So as we said in earlier remarks, and moving that forward in <unk>.

John Leonard: But we're making good progress, as we said in our earlier remarks, moving that forward. And one of the things, you know, as we said earlier that we particularly like about that program is that, you know, this modularity is playing out very much in our favor, we believe. Same lipid structure, same mRNA cargo, and essentially the same guide with the exception of about 20 nucleotides.

One of the things you know, it's as we said earlier that we particularly like about that program is that you know.

Modularity is playing out very much in our favor. We believe same lipid structure same MLR on a cargo and essentially the same guide with the exception of its about 20 nuclear touch so that's given us the ability to move a little further into the cohorts.

John Leonard: So that's given us the ability to move a little further into the cohorts, the cohorts that we began 2001 with. And so we think we'll really get positioned later this year to share information that we have that hopefully corroborates some of the findings that we had with 2001. So stay tuned.

The cohorts that we began 20 of Onewest and so we think we will you know really good position later this year too.

I'm sure our information that we have that hopefully corroborate some of the findings that we had with the 20th one so stay tuned.

Great. Okay. Thanks for taking my questions and I look forward to the update next week.

Maury Raycroft: Great. OK, thanks for taking my questions and I look forward to the update next week. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi, this is Tommy on for Salveen.

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

Hi, This is Tommy on for solving thank you for taking the question I wanted to ask about business development in terms of your overall strategy and whether we should expect to see.

Tommy: Thank you for. I wanted to ask about business development in terms of your overall strategy and whether we should expect to see more deals in 22, and if so, what are you looking for? Yeah, thanks for that question. So we have a strategy, and you asked for a time frame, so let's leave the time frame out, because what we're not going to be able to do is commit to any particular deal within any particular time frame.

In 'twenty, two and if so what are you looking for in a partner. Thank you.

Yeah. Thanks for that question.

So we have a strategy and you asked for a timeframe. So let's leave the timeframe out cause I, what we're not going to be able to do is commit to any particular deal within any particular timeframe, but I think based on what you've seen already.

John Leonard: But I think based on what you've seen already, you should start to get some notion of how we think about our workers. So we are first absolutely laser-focused on our pipeline and those programs that we guide to, that we control or have significant participation in. And that is very much foremost on our minds, and we will always remain focused on that. However, we find that some of the insights that we've gained from the work in our research area are more broadly applicable and go outside the realm of what we can or are able to immediately reduce to practice.

You should start to get some notion of how we think about our work here. So we are first absolutely laser focused on our pipeline and those programs that we guide to that we control or have a significant participation in that.

Is very much a.

Foremost on our minds and we will always remain focused on that.

However, we find that some of the insights.

Insights that we've gained from our work and our research area are more broadly applicable and go outside the realm of what we can or are able to immediately reduce the practice.

John Leonard: And in those cases, we believe that if we can find complementary technology or complement, more importantly, perhaps, complementary biology, We love those partnerships because what that does is it gives us an opportunity to make products more competitive and ultimately serve patients better by combining the insights of two groups as opposed to just one. What we try to do is maintain some significant participation in those products. And I think if you look at the deals we've done now since the first one, which is Advancel last year, in every case, we've retained some significant commercial participation. And our partners like that, and we like that, and we think it's in everybody's best interest.

And in those cases, we believe that if.

If we can find complementary technology or a couple and more importantly, perhaps complementary biology.

We love those partnerships because what that does is it gives us an opportunity to make our products more competitive and ultimately serve patients better by combining the insights of two groups as opposed to just one well we try to do is maintain a sub.

Some significant participation in those products.

If you look at deals we've done now since you know the first one which is I havent fell last year.

In every case, we've retained some significant commercial participation in our partners like that and we like that and we think it's in everybody's best interests. So yeah.

John Leonard: So the idea is have essentially a parallel pipeline that does not consume substantial resources on our end, but leverages the insights and resources of others that are catalyzed by capabilities that we can complement their work with. And when those opportunities arise, we will do them to the fullest extent possible. So just one other element is if you step back and look at it.

The idea is have essentially.

A parallel pipeline that does not consume substantial resources on our end, but leverages, the insights and resources of others.

Ed or catalyzed by our capabilities a week, we can complement their work with and you.

You know when those opportunities arise we will do.

To the fullest extent possible. So yeah, just one mother element is if you step back and look at it.

John Leonard: In addition to our own pipeline now, we have an NK cell partner, which we're really excited about. We have a universal CAR-T effort, which we're really excited about. We've now moved into the autoimmune space, which we think is a wonderful opportunity. And we also have a position in the ophthalmology space. And that, you know, I think when you step back and look at it, is a wonderful way of thinking about how genome editing can really be deployed in ways that are meaningful for patients. So watch us as we go.

In addition to our own pipeline now we.

And NK cell partner, which we're really excited about we have a universal car T effort, which we're really excited about we've now moved into the autoimmune space, which we think is a wonderful opportunity and we also have a position in the ophthalmology space and and that you know.

I think when you step back and look at it as a wonderful way of thinking about how genome editing.

It can really be deployed in ways that are meaningful for patients. So.

What's your sense, we go in and are you now.

John Leonard: And, you know, just you should be confident that we're always looking and we're always thinking about possibilities. The next question comes from Mani. Foroohar with SVB Lyrinc.

You should be consequence that we're always looking and we're always thinking about possibilities.

The next question comes from money.

Through her with S V. B Leerink. Please go ahead.

Hi, Good morning, everyone. This is graco on for Mani. Thanks for taking our questions I have two questions when I E. T D programs and we can go one by one but for the first question on I guess, a sort of going off of june's questions. What theres something you observed.

Greco: Please go ahead. Hi, good morning, everyone. This is Greco on for Mani.

Greco: Thanks for taking our questions. I have two questions for the ATD programs, and we can go one by one. But for the first question, I guess sort of going off of June's question, was there something you observed in the NHP or other preclinical studies that you did with the combo approach that made you guys decide not to advance the combo program but instead go with separate independent programs? Thanks for the question. The answer to that is no.

And each P or other preclinical studies that you did with that combo approach that made you guys decided not to advance the combo program, but instead go with separate independent programs.

John Leonard: In fact, if you go back and look at that study that we presented, It really is two steps, two independent steps. And so what we did in those non-human primates was demonstrate exactly what we're doing in human beings, which is an insertion that produces high levels of the human protein. That remains to be demonstrated, obviously, in the clinic and in the case of the candidate now. But we showed that we could generate those high levels of protein production inserting into the albumin gene. And I think that that's an important point here.

Thanks for the question the answer to that is no in fact it is.

If you go back and look at that that study that we presented.

It really is two steps to independent steps and so what we did in those nonhuman primates was demonstrate exactly what we're doing in human gangs switches say it.

At insertion that produces high levels for the human protein I mean that remains to be demonstrated obviously in the clinic and in the case of the candidate now, but we showed that we could generate those high levels of protein production inserted into the albumin sheets and I think that's an important point here.

John Leonard: And then separately, and separated in time, we went and knocked out the offending Serpent A1 gene that was a key target for what would be causing the liver disease in humans with mutation. And so, you know, it's... Essentially identical to the way we're advancing it in humans. What we're not doing though is taking two investigational agents into a single patient at the same time which we think is prudent and we think it gives us the opportunity again to learn about the strengths and weaknesses, if any, of the various programs that we have before we think about bringing them together into a single patient, but we will always have that possibility down the road.

And then separately and separated in time, we went and knocked out the offending.

Yup, surpassing a one Jason that was a key target for what would be causing the liver disease in humans with mutation.

So you know, it's it's essentially identical to the way we're advancing it in humans.

Not doing though is taking two investigational agents into a single patient at the same time, which we think is prudent and we think it gives us the opportunity again to learn about the strengths and weaknesses if any of the various programs that we have before.

Before we think about putting them together into a single patient, but we will always have that possibility down the road.

Got it and I suspect each a T. D program will have a different scientific and clinical risk profile coming from both the approach and the target patient population can you provide some insight and color around these risk profile differences between these program.

John Leonard: Got it. And I suspect each ATD program will have a different scientific and clinical risk profile coming from both the approach and the target patient population. Can you provide some insight and color around these risk profile differences between these programs?

Yes.

Well if they are different in the sense that a knock.

John Leonard: Well, they are different in the sense that a knockout, 2003, is yet another example of the two knockout programs already in the clinic. And so the principles that we're learning for 2001 and now 2002, we think are going to be immediately applicable to 2003. And so just by virtue of having more experience in the clinic, we think that that gives us a, you know, just a clearer focus on, how that drug is likely to perform. You know, the patient population is different, of course, and so we have to bear that in mind as we proceed. In the case of 3001, this is an insertion program.

Knockout <unk> 23.

Is yet another example of the two knockout programs already in the clinic and so you know the principles that we're learning for 'twenty, one and now 20 O. Two we think we're gonna be immediately applicable to 20th tray and so just by virtue of having more experienced.

Clinic, we think that that gives us a you know just a clear focus on how that drug is likely to perform.

The patient population is different course, and swift to bear that in mind as we proceed.

John Leonard: So you'll remember that these are hybrid programs where the insertion is both the combination of an LNP to target the gene where the insertion is going to take place. And then the template is provided in the form of AAV. That's new clinical territory for us. And we're doing the requisite preclinical work. Obviously, we presented data already in terms of non-human primates.

In the case of 31.

This is an assertion program so you'll remember that these are.

Our hybrid programs, where the insertion is both the combination of an L. M. P to target the gene where they can search is going to take place and then the template is provided in the form of a D. A.

New clinical territory for us and where.

We're doing.

Doing the requisite preclinical work, obviously, we presented data already in terms of non human primates, we continued to build on that with our preclinical package for regulatory purposes.

John Leonard: We continue to build on that with our preclinical package for regulatory purposes. But, you know, we just don't know as much in humans yet. And so I'd have to say that, you know, there's just more uncertainty that comes with that program.

But yeah, we just don't know as much in humans, yet so I'd have to say that you know, there's just more uncertainty that comes with that program, but.

We will apply the same logic and principles that we applied with.

The other programs before that so.

Hopefully our preclinical studies will serve us well.

Got it that's all from me I'll hop back into queue. Thank you.

John Leonard: But we will apply the same logic and principles that we applied with, you know, the other programs before that. So hopefully, our preclinical studies will serve us well. Got it. That's all from me. I'll have to talk in the queue.

The next question comes from swap new metal car with Piper Sandler. Please go ahead.

Greco: Thank you. The next question comes from Swapnew Medicar with Piper Sandler. Please go ahead. Good morning.

Hi, Good morning. Thank you for taking my questions. One question on 5001, so given that bank Blackstone.

Swapnew Medicar: Thank you for taking my questions. One question on 5001. So given that Venclexta is not applicable in unfit AML patients, And that might be the case with 5001, which may be limited to similar patient population due to conditioning regimen.

It's not applicable and unfit AML patients.

And that might be the case with 5001, which may be limited the similar patient population to the conditioning regimen can.

Swapnew Medicar: Can you talk about the company's strategy to differentiate versus some of the competitors in that space and how you could address a broader AML patient population? It's what I got everything you I think at the last three quarters of your comment, but if you've made a statement at the beginning that we couldn't quite hear about other agents, I think, if you could just restate that. Sure, yeah, so just like when Plexi, it's approved, and it's not applicable in unfit AML patients.

Can you talk about the company's strategy to differentiate what is the some of the complex it other than that space and Oh Youll hear about it.

Patient population.

It's why I, probably got everything you I think it's the.

The last three quarters, you can comment, but if you you've made a statement at the beginning.

We couldn't quite hear.

Our other agents. So I think if you could just restate that.

David Lebwohl: And given that 5001 requires a conditioning regimen, so it might be limited in similar smaller number of patients. So like, what's the strategy to go into a broader patient population? How could 5001 be differentiated in that space?

Sure Yeah, so just like when when flex day, if it's approved and it's not applicable and unfit AML patients.

And given that 5001 requires a conditioning regimen and so it might be limited in similar smaller number of patients. So like what's the strategy to go into a broader patient population, where 5000, what would differentiate that at that space.

David is that something you want to talk about I mean, I think so it's not just a blip.

David Lebwohl: David, is that something you want to talk about? I mean, I think, just by broad strokes, we're in the early stages here, where, you know, the ongoing clinical study is collecting safety data and PK data and early response data in patients with low disease levels and higher disease levels. The thinking is, to the extent that, you know, we affect blast counts with that safety profile, that will determine the path where we go.

Broad strokes, we're in the early stages here where the.

The ongoing clinical study is collecting safety data and and PK data in an early response data in patients with <unk>.

<unk> low disease levels and higher deletes disease levels.

The thinking is to the extent that we affect blast counts.

And with that safety profile that will determine the path, where we go in and.

I don't know David if you want to add anything about conditioning regimens and how that might affect the trajectory of the program I think there's a question here.

And I think Stephens, David I think that your concern is that unfit patients would not be able to receive the conditioning regimen and.

David Lebwohl: And I don't know, David, if you want to add anything about conditioning regimens and how that might affect the trajectory of the program. Thanks, David. I think that your concern is that unfit patients would not be able to receive the conditioning regimen. And remember that unfit patients are unable to receive intensive therapy, bone marrow transplant, et cetera. So this is a group of patients who was older, but it doesn't mean that they can't necessarily receive preconditioning of the type that's used for CAR T or TCR therapies and then receive TCRs, which themselves are expected to be more better tolerated than CAR T therapies.

And remember that an unfit patients are unable to receive intensive therapy bone marrow transplant et cetera. So this is a group of patients who it.

That was older but it doesn't mean that they can't necessarily receive precondition hang up this type of choose for car T or TCR therapies, and then receive tcr's, which themselves are expected to be more a better tolerated and car T. Therapies. So I think that we will be able to.

Swapnew Medicar: So I think that we will be able to, at some point, be treating patients who might otherwise be considered unfit for a bone marrow transplant. Got it. Thank you. And then I have one question on 2001.

Some point be treating patients who might otherwise be considered unfit for bone marrow transplant.

Got it. Thank you and then I have one question on 2001 I wanted to ask about that they pay expectations for next week.

Swapnew Medicar: I won't ask about the data expectations for next week, but like there remains to be like some concern regarding the cardiomyopathy part of the trial, given the bridge bio failure. So like, are there like any updated thoughts on your strategy in terms of like patient stratification or endpoint selection to get an outcome that is more aligned, like or like similar to taphameris rather than bridge bio? We think about it a lot and we'll be happy to talk about it on Monday. Got it.

But that remains to be like some concern regarding the cardiomyopathy part of their trial, given the British biophilia or so when they are there like any updated parts on your strategy in terms of the patient stratification or endpoint selection.

Get an outcome that is more aligned like on like similar to the families rather than other than British bio.

We think about it a lot and we'll be havent talked about it on Monday.

Got it thank you for taking my questions.

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

Swapnew Medicar: Thank you for taking my question. The next question comes from Dagon Ha-Rustiful. Please go ahead. Great, good morning. Thanks for taking our questions and congrats on all the progress. I'll also stick with non-2001.

Dagon Ha-Rustiful: With regards to 2002 specifically, you mentioned in your press release, there's a Quad AI meeting. So wondering what we can expect there, given your announcement of interim cut in the second half. And as it pertains to the second half update, the press release also talks about biomarkers and preliminary proof of concept. So I think in our prior calls, you've mentioned that it won't necessarily be reductions in attack frequency, but anything else that we should keep an eye out for, and also what kind of safety events should we kind of discount as disease-related versus drug-related. Thank you very much.

Great. Good morning, Thanks for taking our questions and congrats on all the progress I'll also stick with non 2001 with regards to 2002, specifically you mentioned in your press release, there's a quality I meeting. So wondering what we can expect there given your announcement of interim cut and the second half.

And as it pertains to the second half up day. The press release also talks about Biomarkers and preliminary proof of concept. So I think in our prior calls you've mentioned that it won't necessarily be reductions in attack frequency, but anything else that we should keep an eye out for are and also what kind of safety events should we kind of discount this disease related.

Versus a drug related thank you very much.

John Leonard: Yeah, thanks for the question. I mean, with respect to 2002, we're not guiding to any particular data set, We will share information in the second half, and as we determine the appropriate place and time and all that, we'll give advance notice on that. What I would do is, as I said earlier, is look to what we presented in 2001 as a guide for the sort of information to expect for 2002. Attack rates are collected over some observation period, obviously in advance, and if you're looking for a therapeutic benefit, the longer observation period you have after that, the more you're able to speak to attack rates.

Yeah. Thanks for the question I mean with respect to the 20th two we were not.

[noise] guiding to any particular datasets.

We will share information in the second half and as we determined the appropriate place and time and all that will give advance notice on that.

Hum.

What I would do is as I said earlier is look to what we presented in 'twenty one as a guide for the sorts of information to expect for 'twenty two.

The attack rates are collected over some observation period.

Obviously in advance.

And if youre looking for therapeutic benefit the longer observation period to have after that is the more you're able to speak to attack rates.

John Leonard: We'll collect that information, but that is not the primary purpose of what we're doing in this first phase study. We're looking for the effects on the target protein, calocrine, which is, you know, the offending agent in this case. And the focus should be, the way you should be thinking about this, focus should be on how much of an effect we get on that protein knockdown. And then the way we do it is very similar to what we've done with the PTR program, extrapolate from the work of others in terms of what we anticipate is likely to be the clinical benefit and use that as our guide for thinking about the ultimate clinical utility.

We'll collect that information, but that is not the primary purpose of what we're doing in this first phase study, we're looking for the effects on the target protein cattle Crane, which as you know the offending agent in this case and the focus should be the way you should think about this focus.

It should be on a how much of an effect, we get on that protein knockdown.

And then the way we do it is very similar to what we've done with the PTR program extrapolate from the work of others in terms of what we anticipate is likely to be the clinical benefit and use that as a guide for thinking about the ultimate clinical utility so.

John Leonard: So, we'll talk more about that as the year unfolds, but that's the way I would think about it for now. And anything with regards to quad AI meeting? I don't think we've specifically talked about what we're going to present at which meeting yet.

We'll talk more about that as the year unfolds, but that's the way I would think about it for now.

Okay.

And anything with regards to quality I'm eating.

I don't think we've set specifically talked about a wash.

What we're gonna presented which meeting yet so again as that comes into greater focus.

John Leonard: So again, as that comes into greater focus, but we will provide additional information on our website once the meeting specifics are available. And that's how we'll talk about what we're going to present and exactly when. But at this point, we're not guiding to anything beyond that. That information, the time and place of the meeting, when the meeting permits to talk about, we'll make it available on our website. Great. See you guys on Monday. Thank you very much. See you guys on Monday.

But we will well will provide some additional information on our website.

Once the meeting.

The specifics are available and that's how we'll talk about what we're gonna presenting and you know exactly when but at this point, we're not guiding to anything beyond that that information.

Time and places the meeting.

When the meeting permits just talking about well, we'll make it available on our website.

Great. So you guys on Monday, Thank you very much.

In Q.

And remind you to kindly limit yourself to one question. The next question comes from Luca <unk> with RBC. Please go ahead.

Dagon Ha-Rustiful: Thank you. And a reminder to kindly limit yourself to one question. The next question comes from Luca Issi with RBC. Please go ahead. Oh, great. Thanks so much. I'll try to behave and not ask a question about Monday.

Oh, great. Thanks, so much I tried to behave and not ask a question about Monday, and maybe I'll. Let me one question, but an exciting data for the bio railroad truck trophic lipid nanoparticle last year I'm wondering if you can comment on what's next for that program. Thank you.

Luca Issi: Maybe I'll limit to one question, but exciting data for the Bonne Mare tropic clipping on a particle last year. I'm wondering if you can comment on what's next for that program. Thank you. It's an important target for us. One that we're very, very actively engaged in. We view that as a tissue that, after the liver, is one where LMPs will service well.

It's an important target for us one that we're very very actively engaged and we view that as a tissue that after the liver is one where ellen piece will serve us well and our research team is actively.

John Leonard: And our research team is actively working to translate that work into the next level of species. And when we have more data to present, we'll do so at the appropriate scientific meeting. Thanks so much.

Working on a working to translate that work into the next level of species well, we have more data to present.

We will do so at the appropriate scientific.

Thanks, so much.

Sure.

Yes.

The next question comes from Mike King with H C. Wainwright. Please go ahead.

Mike King: Sure. The next question comes from Mike King with HC Wainwright. Please go ahead. Hey, thanks. Good morning, guys.

Hey, Thanks, good morning, guys.

Mike King: Please want to ask you, in light of some of the regulatory and, Clinical challenges that have been seen recently with ex vivo modalities, just wondering how we should think about what differences Intellia will bring to the space, not only with respect to your proprietary programs, but also with respect to Vancell and Kyverna. Do you have anything in mind, Mike, that you want us to speak to, or? Well, there's been clinical holds placed on, yeah, there have been clinical holds placed on some programs. You know, there have also been durability challenges with some others.

I just wanted to ask you in light of some of the regulatory and Clint.

Clinical challenges that had been seen recently with our ex vivo modalities just wondering how we should think about.

But differences intaglio will bring.

To the space.

Not only with respect to your proprietary programs, but also with respect to advanced selling and Corona.

[noise] drip anything in mind, Mike that she wants to speak to her well theres been very general question placed on yeah, they've been clinical hold placed on some programs I. You know there have also been durability challenges with some others. So I'm just I guess, that's kind of framework in my question.

Yeah. So thanks remember that.

John Leonard: So, I'm just, I guess that's kind of the framework of my question. Yeah, so thanks. Remember that 5001 is up and running.

One is up and running we have in India, and the U S and <unk>.

We are.

John Leonard: We have an IND in the US and the, regulators have seen our package and the preclinical work that goes with it. And, you know, despite, What may have been the case with others, which I can't speak to, they've been satisfied with, you know, all the preclinical work that we've done, and so we're actively enrolling patients. You know, I'd go back to the overall approach that we've tried to take in this space.

Regulators have seen our package in the preclinical work that goes with it and you know despite.

What may have been the case with with others. So I can't speak to them they've been satisfied with all the preclinical work that we've done and so we're actively enrolling patients.

You go back to the overall approach that we've tried to take in this space.

John Leonard: This is how we think about the biology and using genome editing, et cetera. We've gone all the way back to the beginning in terms of asking very fundamental questions about how to get material into cells, for starters, in contrast with the preponderance of programs which use electroporation. We use lipid nanoparticles.

This is how we think about the biology and using genome editing et cetera, We've gone all the way back to the beginning in terms of asking very fundamental question, just about how to get material into cells for starters.

In contrast, with.

The preponderance of our programs, which use electroporation.

We use lipid nanoparticles, we presented data.

John Leonard: We presented data that electroporation, no matter what your editing modality is, introduces genome breaks in translocation, and that is something that happens in a predictable fashion but with unpredictable results, and you know the work that we've done with the banana particles uh it's just different from that you essentially have uh levels of uh you know Translocations are breaks that are indistinguishable from cells that have never been, you know, transduced in the first place. So it starts there.

<unk> electric operations no matter Whats your mode editing modality is introduces a cheat on brakes and translocations and.

And that is something that happens.

In a predictable fashion, but with unpredictable results and you know with the work that we've done with lipid nanoparticles.

It's just different from that you essentially have.

Levels of <unk>.

Translocation that breaks that are indistinguishable from cells have never been.

<unk> in the first place so it starts there.

John Leonard: And then it relates to, you know, the quality of the guides, the sequential nature of the work that we do as we introduce different genetic changes, and we carefully monitor that, measuring as we go, the effect. And what we've presented is that, in our judgment, distinct from what others have seen, you have very, very low levels of off-target effects, A, and B, very low levels of, you know, disturbed genetic architecture. So we think that that puts us in a good position just, you know, with the basics. Now, with respect to durability, for those Allo programs where we've seen graphs lost in a matter of weeks, We don't find that surprising outcome because it's well known that with reconstitution of the immune system. Hi!

And then it relates to the quality of the guides the sequential nature of the work that we do as we introduce a different.

Genetic changes and we carefully monitor that majoring as we go the fact and what we've presented is that in our judgment distinct from what others are saying.

You have very very low levels of off target effects, a and b are very low levels of disturbed genetic architecture. So we think that that puts us.

In a good position just with the basics.

Respected durability for.

For those allo programs, where we've seen graphs lost in a matter of weeks.

You don't find that surprising outcome, because it's well known that with reconstitution of the immune system.

Uh huh.

John Leonard: Bye! NK cells remove cells that lack class one and, you know, we've received that in space, I think, with other programs that, You know, our judgment falls short of what we're trying to do, where by taking a different approach, and we'll share more about that as the year goes on, with our Allo program, that's not going to happen. We've presented data preclinically to show that, in fact, those cells, you know, they're treated the way we do it.

NK cells remove cells that lack of class one and you know.

We're seeing that space, so I think with other programs.

That.

Our judgment falls short of what we're trying to do we're taking a different approach and we will share more about this year goes on.

With our Allo program, that's not going to happen, we presented data pre clinically to show that in fact those cells, they're treated the way we do it withstand and her at susceptible 10-K immediate attacks. So we think that that augurs well for not just having the.

John Leonard: So we think that that augers well for not just having, you know, the material ready when a patient presents, but also having persistence of the graft, which we think is really important for efficacy. And ultimately, we think that that will address one of the fundamental problems in the space, which is the cost of goods.

Material ready when a patient presents but also.

Having persistence of the graft, which we think is really important for efficacy and ultimately we think that that will address one of the fundamental problems in the space, which is the cost of goods.

John Leonard: So all together, we're hoping with the Allo programs we're moving forward, we'll have the clinical data that addresses those points and shows that our thinking does, in fact, play out the way we believe it will. Okay, appreciate the answer to the question. The next question comes from Steve Seedhouse with Raymond James. Please go ahead. Hi there, this is Ryan Dechner on for Steve Seedhouse.

So altogether, we're hoping with the allo programs. We're moving forward, we will have the clinical data that addresses those points.

Those that are thinking does in fact play out the way we believe it will.

Okay I appreciate the answers the question.

Sure. The next the next question comes from Steve Steve House with Raymond James. Please go ahead.

Hi, there this is Ryan Deschner on for Steve actually go.

Ryan Dechner: For NTLA-5001, you noted that you began enrolling AML patients. Given this is an autologous therapy, could you talk about the vein-to-vein time, and do you anticipate problems with patients progressing long-term therapies? Well, we will find the vein-to-vein time directly in our clinical programs as we proceed, but remember, we've shown in our preclinical work that we expect it to be around three weeks. That's all aspects considered, and we benefit from the light effect of the LMPs, and we've shown that cells that have been transduced grow quickly and preserve the viability, and we think that that translates into benefits in terms of the time between removing cells and returning them. As we get our clinical data, we'll speak more directly to what we actually measure, but preclinically, we would judge it to be around three weeks.

For antibody 5001, you noted that you begin begun enrolling AML patients. Given this is a top of autologous therapy could you talk about the vein to vein time do you anticipate problems with patients progressing or cell therapies.

Well, we will find the vein to vein time directly.

Programs as we proceed but remember with shell on our in our preclinical work that we expect it to be around three weeks. That's you know all aspects are considered and we benefit from the light Oh, well the late effect the Olympia.

And we've shown that cells have been transduce grow quickly and preserve the viability and we think that that translates into benefits in terms of the time between removing cells from returning them.

So as we get our clinical data will speak more directly to the well, we actually measure, but pre clinically we would judge it to be around three weeks.

Wonderful. Thank you very much also real quick I'm wondering if you have any sort of timeline for an update on potential progress you've targeted indications for your base editing technology.

John Leonard: Also, real quick, I'm wondering if you have any sort of timeline for an update on potential progress and targeted indications for your base editor? Today, we're not in a position to guide you to that, but we like what we've got. As mentioned earlier, we think the base editor is ideally suited to multiplex knockouts in the Ex Vivo setting.

Yeah.

Today, we're not in a position to guide to that but we like what we've got and as I.

I mentioned earlier, we think the base centers ideally suited to multiplex knockouts.

Vivo setting and that's one of the things that we think about as we have more complex edits in the ex vivo space. So.

As programs advance will talk a little bit more about that.

Excellent. Thank you very much.

The next question comes from Jay Olson with Oppenheimer. Please go ahead.

John Leonard: And that's one of the things that we think about is we have more complex edits in the Ex Vivo space. So as programs advance, we'll talk a little bit more about that. Excellent, thank you very much. The next question comes from Jay Olson with Oppenheimer. Please go ahead. Oh, hey, congrats on the progress and thanks for taking the question. Can you talk about the gating factors for filing the IND for 3001?

Oh, Hey, congrats on the progress and thanks for taking the question can you talk about the gating factors for filing the I N D for <unk>.

John Leonard: And then related to that, can you also comment on the size of the commercial opportunity for 3001 and 2003? So we break 30.01 into a couple of parts, the first, remember this is a hybrid application where we have the LNP coupled with the AAV. So the LNP in many respects is well advanced because it follows the work that we've done previously. We know that that program is, we generated data, so we're well down the road. In the case of 30.01, a lot of this work has to do with the AAV and the template and some of the tax work that goes with that.

30 year, one and then related to that can you also comment on the size of the commercial opportunity for 31 and 23.

So we break 31 into a couple of parts. The first remember this is a hybrid.

Applications, where we have C O M P coupled with T. I a P. So the L. M P.

In many respects is well advanced because it follows the work that we've done previously and we know that that program is we generated data. So we're well down the road in the case of <unk> 31, a lot of this work has to do with the a V and the template and some of the.

Tox work that goes with that so I'm not going to give dates or anything like that but that's the nature of the work that's underway.

John Leonard: So I'm not going to give dates or anything like that, but that's the nature of the work that's underway. Great. And can you please comment on the size of the commercial opportunity for 3001 and also 2003? Well, we believe that there's substantial opportunity in the Alpha-1 space generally, and we think it's measured well in excess of a billion dollars, and depending on the reports you read, it's plural, a billion applies, but at this point, we're not going to come up with a particular number.

Great and can you. Please comment on the size of the commercial opportunity for 30 year, one and also 'twenty Oh sorry.

Well, we believe that there's substantial opportunity in the in the held for one space generally.

And we think it's measured.

It well in excess of $1 billion and depending on the reports you read it.

Plural billions supplies, but at this point, we're not going to come up with a particular number I think it's important to get more data.

John Leonard: I think it's important to get more data in terms of how we think the actual drug is going to perform, and that's going to really determine where and how it plays, and we'll have a better line of sight to what is that ultimate value, but I would point out that existing therapy for patients is inadequate. Patients progress and die on replacement therapy, which is essentially all that's available to them, and in the case of the liver setting, there's almost no effective therapy that's available for these patients currently, so we think that it's almost a wide-open space at this point.

Data in terms of how we think the actual drug is going to perform and that's going to really determine where and how it plays out we'll have a better line of sight to what is that ultimate value.

But I would point out that the existing therapy for patients is inadequate.

<unk> progress and die I'm replacement therapy, which is essentially all of its available to them and in the case of the liver setting there's almost no effective therapy. That's available for these patients are currently so we think that it's almost a wide open space at this point.

Great. Thanks for taking the questions.

John Leonard: Great, thanks for taking the questions. Sure. The next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi, thanks for taking my questions. I have a question on the HAE program and a very, very brief question on the AML program. So on the Phase 2 study of NTLA 2002, for the Phase 2 portion of that study, I noted that you had designed two cohorts, two different dose levels, which is in contrast to your TTR program.

Sure.

The next question comes from you know non Jew with Wells Fargo. Please go ahead.

Hi, Thanks for taking my questions I have a question on the H E program and a very brief question on the AML program. So on the phase two study of NTR late 2002.

John Leonard: Is there anything particular about this target in HAE that makes the dose selection maybe a little different, or is there some other reason? And the very brief question on AML is, are the two arms, the lower disease burden arm and the higher disease burden arm, are they going in parallel, or is one going into the clinic first? And could we expect any data from either arm this year?

For the phase two portion of that study I noticed that you had designed two cohorts a different dose levels, which is in contrast to your.

TCR program is there anything particular about this target.

E that makes that don't just selection, maybe a little different.

Or is there some.

Some other reason.

And the very brief question on AML is are the two arms the lower B. These burden arm and a higher disease burden on them are they going in parallel or is one going going into the clinic first and could we expect any data from either arm. This year. Thank you.

Well I'll do the second question, David Lebel can address the logic of those.

Yanan Zhu: Thank you. I'll do the second question and David Lebowitz can address the logic of those two cohorts in the HEE program, but the short answer to the ML program is that they're progressing in parallel, and we're focused on enrolling the study now, we're not, Committing to a data disclosure, it's really going to be a function of the rate at which patient data accrues and what we have to look at. And back to what we've said in our other programs, we will apply the same sorts of principles that we've had about disclosing that data.

Two cohorts in the a T program.

But the short answer to the email programs that are progressing in parallel.

And we're focused on enrolling the study now were not.

Meaning to a data disclosure, it's really going to be a function of the rate at which patients.

Beta crews in and what we have to look at it.

Back to what we've seen or other programs, we will apply the same sorts of principles that we've had.

About disclosing that data and as soon as we can we will but it's really a function of getting the patients in the first place. So David do you want to say a word about how you think about the.

Yanan Zhu: And as soon as we can, we will. But it's really a function of getting the patients in the first place. So, David, do you want to just say a word about how you think about the different cohorts in the HAE program? Yeah, hi, thanks.

Different cohorts in the HIV program.

David Lebowitz: So the we do think somewhat differently about dosing in the HAE program and the TTR program. So in the TTR program is good evidence getting to as low, that amounts of TTR as possible could be beneficial for patients. There's a good proportionality between that reduction and the clinical benefit that we'll see in patients. So, you know, you'll see the data Monday where we're going with that. On the HAE program, there's more data that with lesser reductions, even just 80%, as we saw, you know, an 80% reduction pre-calocrine, you get very major reductions and attacks on the aims of, you know, upwards of 90% or higher.

Yeah. Thanks, So we do think somewhat differently about dosing in the atrium programming.

Teach you our program so in the TCR program is good evidence getting too low.

About amounts with T T R as possible it could be beneficial for patients and that was a good proportionality between that reduction and the clinical benefit that we'll see in patients. So you know you'll see the data Monday, where we're going with that.

E program, there's more data that with a lesser reductions even just 80% as we saw no.

And 80% reduction in pre collar crime, you've got very major reductions in attacks.

Ms of upwards of 90% or higher so we will be looking very carefully at what what dose we need to go forward with.

David Lebowitz: So, we will be looking very carefully at what dose we need to go forward with. The phase two dose does have the potential to have two different dose levels, though, of course, we could also go forward with a single dose level depending on what we find during the dose escalation portion.

The phase two does have that potential to have two different dose levels, though of course, we could also go forward with a single dose level, depending on what we find during the dose escalation portion.

Very helpful. Thank you.

The next question comes from Silvan <unk> with JMP.

Yanan Zhu: The next question comes from Silvan Tuerkcan with JMP. Please go ahead. Good morning, and thanks for taking my questions and congrats with the progress. I just had a brief question about 5001.

Please go ahead.

Good morning, and thanks for taking my questions and congrats with the progress.

Silvan Tuerkcan: You kind of touched on, you know, changes, potential changes in persistency that you may have with your manufacturing. But could you tell us, if you're exploring redosing in this trial initially, or if that's initially off the table, and you will consider potential, changes like consolidation dosing that we've seen in aloe cartilage, for even thinking about that. That would be great. David, what are your plans for re-dosing, if any, in the Phase 1 trial for 5011? So we call the TCO-1 as an autologous program, so we really don't anticipate any issues with persistence in this program, so right now it is planned as a single dosing.

I just had a brief question about 50 of one you kind of touched on you know changes potential changes in persistency that you might have with your manufacturing.

But could you tell us if you're exploring re dosing in this trial initially or if that's initially off the table and you will consider potential changes.

Changes like consolidation don't think that we've seen in our car Ts for even thinking about that that'd be great. Thank you.

David what are your plans for re dosing as any in the phase one trial for stealing.

Yes, so we call it 50 or what is that autologous program. So we really don't anticipate any issues with persistence in this program. So right now it is planned as a single a single dosing.

Thank you very much.

Yeah.

David Lebowitz: Thank you very much. Okay, and I believe that there's time for one more questioner today. That will be WG, Chatterpadhyay with Guggenheim. Please go ahead. Hi, this is Ry Forseth. I'm for Debjet. Two quick questions.

And I believe that there is time for one more question are today that.

That will be Doug Jeet.

<unk> <unk> with Guggenheim. Please go ahead.

Hi, This is Ryan for Seth on for Deb Jet two quick questions, what's the anticipated capacity utilization and the GMP facility comes online in 2024, and secondly for 3001, what's the consequence of knocking into the albumin.

Ry Forseth: What's the anticipated capacity utilization when the GMP facility comes online in 2024? And secondly, for 3001, what's the consequence of knocking out the albumin gene on tissue albumin levels and circulating albumin levels? We'll do the 30th one first.

Jean on tissue albumin levels in circulating albumin levels.

[laughter] well do the 30th one first in the preclinical work, which we've done a we've.

John Leonard: In the preclinical work which we've done, we've had a de minimis effect on albumin. What we're not doing is knocking into every single albumin locus. That's something we've watched very, very carefully. One of the virtues of the albumin locus is that it's probably the most highly expressed gene in the body. You get a lot of drive of the gene that you introduce there. You can accomplish exactly what you need, at least in non-human primates, high levels of circulating protein.

We've had a de minimis effect on albumin.

What we're not doing is knocking into every single albumin locus, that's something we watch very very carefully.

And one of the virtues of the albumin locus is that it's probably the most highly expressed gene in the body and so you get a lot of drive of the you know the gene that you introduced there. So you can accomplish.

Exactly what she needs at least in nonhuman primates high levels of circulating protein that.

John Leonard: So it achieves the same levels of protein that humans produce while still preserving the normal function of the alveoli. So we think that that's an ideal place to crop in that particular insertion. With respect to the GMP facility, we're not in a position yet to talk about capacity and utilization down the road. But I'll say this: we're really excited about the resource. It's a substantial facility that's 140,000 square feet

Achieves the same levels of a protein that humans produce while still preserving normal functionally albumin alone. So we think that that's an ideal place to.

Crop in that that particular insertion with respect to the GMP facility.

We're not in a position yet to talk about capacity and.

And utilization down the road I'll say that we're really excited about the resource. It's a substantial facility that you know its 140000 square feet.

John Leonard: If you think about that and judge some of the other facilities that you see in our space, you'll realize that that is a substantial commitment on our part. We think it's going to put us in an excellent position to carry out not only what we're working on, but support some of those collaborations as appropriate as we go forward, and provide a really important resource to our increasing research efforts as well. So it's just something that we're all excited about, and as our work proceeds, I'm sure we'll be in a position to tell you a little bit more about our plans for that facility.

Think about that and judge some of the other facilities that you see.

In this space, you'll realize that that is a substantial commitment on our part.

And we think that's going to put us in an excellent position to carry out not only what we're working on but it supports the most collaborations as appropriate as we go forward and.

Ill provide a really important resource to our increasing research efforts as well. So it's just something that we're all excited about and as you know our work proceeds.

I'm sure we'll be in a position to tell you a little bit more about our plans for that facility. So thanks for watching and we appreciate that.

Ian Karp: So thanks for watching, and we appreciate that. 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. Great, thanks so much and thanks everyone for joining us today and for your continued interest and support in Intellia. We look forward to updating you on the progress and we hope to see many if not all of you at our NTLA 2001 Investor Event, which is next week on September 28th at 4.30 p.m. Eastern Time. So see you then and have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect. © BF-WATCH TV 2021 © BF-WATCH TV 2021 © BF-WATCH TV 2021

Thank you.

Sure. 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.

Great. Thanks, so much and thanks, everyone for joining us today and for your continued interest and support and tell you. We look forward to updating you on the progress and we hope to see many if not all of you at our 2020 , one investor event, which is next week or 28th at 430 P. M. Eastern time, So see you then.

And have a great day.

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

Yeah.

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Yeah.

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