Q2 2021 Intellia Therapeutics Inc Earnings Call

[music].

Good morning, and welcome to the <unk> Telia Therapeutics second quarter 2021 financial results Conference call. My name is Jason and I'll be your conference operator today.

Jason: Good morning, and welcome to the Intellia Therapeutics second quarter 2021 Financial Results Conference Call. My name is Jason, and I will be your conference operator today. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press Star Zero on your telephone keypad.

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

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

Ian Karp: Following formal remarks, we will open the call up for questions. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Antelia. Please proceed. Thank you, and good morning, welcome to Intelia's second quarter 2021 earnings call. Earlier this morning, Intelia issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call.

Following formal remarks, we will open the call up for questions. This conference is being recorded at the company's request and will be available on the company's website. Following the end of the call I will now turn the conference over to Ian Karp Senior Vice President of Investor Relations and corporate communications at until you. Please.

Proceed.

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

Ian Karp: This release can be found on the investors and media section of Intellia's website at InteliatX.com. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during the call, Intelli Management may make certain forward-looking statements and ask that you refer to our SEC filings available at SEC.gov for discussion All information presented on this call is current as of today, and Intelia undertakes no duty to update this information unless required by law. Joining me on the call today are Dr. John Leonard, Chief Executive Officer, Dr. David LeBwall, Chief Medical Officer, Dr. Laura Scep Lorenzino, Chief Scientific Officer, and Glenn Goddard, Chief Financial Officer.

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

At this time I'd like to take a minute to remind listeners that during the call and Telia 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 you undertakes no duty to update this information unless required by law.

Joining me on the call today are Dr. John Leonard Chief Executive Officer, Dr. David Lebel, Chief Medical Officer, Dr. Laura Sepp Laurens, Dino Chief Scientific Officer, and Glenn Goddard, Our Chief Financial Officer on.

Ian Karp: On today's call, John Milleed will discuss the company's second quarter and recent business highlights, followed by David, who will provide an update on clinical efforts surrounding NTLA 2001. Lara will then recap the company's R&D progress, followed by Glenn, who will review Intellia's financial results for the. John will then make some closing remarks, and we'll open up the call for questions. With that, let me turn the call Thank you, Ian, and thank you all for joining us.

On today's call John will lead with the company's second quarter and recent business highlights followed by David who will provide an update on clinical efforts surrounding N. T. L. A 20 O on lateral will then recap the company's R&D progress followed by Glenn who will review <unk> financial results for the quarter. John will then make some closing remarks, and we'll open up the call for Q&A.

With that let me turn the call over to our CEO John.

Thank you Ian and thank you all for joining us today.

John M. Leonard: The past few months have been incredibly exciting for Intellia, as well as for patients battling diseases that may be addressable with their genome editing therapy. Most notably, in June, we became the first company to report clinical data for systemically delivered CRISPR-based therapy and patients. This milestone represents a significant advance in our mission to develop curative genome editing, and in Pellia, we've set out to build the broadest and deepest toolbox to fully realize the promise of revolutionary CRISPR-based medicine.

Few months have been incredibly exciting for both <unk> as well as for patients battling diseases that may be addressable with their genome editing therapies.

Most notably in June we became the first company to reported clinical data for systemically delivered CRISPR based therapy in patients with.

This milestone represents a significant advance in our mission to develop curative genome editing treatments in.

And until we've set out to build the broadest and deepest toolbox to fully realize the promise of revolutionary CRISPR based medicines to.

John M. Leonard: To that end, our platform deploys differentiated, modular solutions across InVo and Exvivo Therapeutic Applications of our Nobel Prize-winning technology. For genetic disease, we're leveraging a lipid nanoparticle or L&P-based delivery system to selectively inactivate disease-causing genes or precisely search for the desired protein. Our exvivo approach is designed to produce a homogeneous, robust cell product that epitomizes a patient's natural immune system to eliminate cancer across these

So that in our platform deploys differentiated modular solutions across from vivo index vivo therapeutic applications of our Nobel Prize winning technology.

For genetic diseases, we're leveraging a lipid nanoparticle or LNP based delivery system to selectively inactivate disease, causing genes.

More precisely insert genes to produce desired proteins.

Our ex vivo approach is designed to produce a homogeneous robust sell product that he <unk> the patient's natural immune system to eliminate can't yourselves across these efforts we've made significant progress advancing our full spectrum strategy since last quarter's call.

John M. Leonard: We've made significant progress advancing our full spectrum strategy since last quarter's call. Our landmark data presented in June highlighted the interim clinical data from the first two cohorts of the dose escalation portion of our ongoing phase one trial for NTI 2001. These data indicate encouraging safety and dose-dependent protein knockdowns. In the second dose level, treatment with NTLA 2001 and the three patients in the cohort led to a mean serum TTR reduction of 87% at day 28, with a maximum 96% reduction.

Our landmark data presented in June highlighted the interim clinical data from the first 2 cohorts of the dose escalation portion of our ongoing phase 1 trial for <unk> 20 O..1.

These data indicate an encouraging safety profile and dose dependent protein knockdown response, and the second dose level treatment within till late 'twenty, 1 and the 3 patients per cohort led to a mean serum TCR reduction of 87% at day 28, with a maximum 96% production.

John M. Leonard: Notably, these results exceed the current standard of care for ATTR amyloidosis patients with polyneopopin, which was generally well tolerated by the six patients included in the interim analysis with no serious adverse events by day 201. We view this as a profoundly important outcome for patients, for TELIA, and for medicine. These positive results not only support NTLA 201's therapeutic potential as a one-time treatment for ATTR amyloidosis but also offer proof of concept for our non-viral delivery platform, giving us added confidence to pursue other targets to treat diseases that originate in the liver via reproducible development.

Notably these results exceed the current standard of care for <unk> amyloidosis patients with Polyneuropathy at both dose levels until late 'twenty..1 was generally well tolerated by the 6 patients included in the interim analysis with no serious adverse events by day 28, we view this as a profile.

On the important outcome for patients from Telia and from Edison.

These positive results not only support until late 'twenty one's therapeutic potential as a 1 time treatment for <unk> amyloidosis, but also offer proof of concept for our non viral delivery platform.

It gives us added confidence to pursue other targets to treat diseases that originate in the liver via reproducible development path.

John M. Leonard: More broadly, we believe these results open a new era in medicine in which curing genetic disease made me within RE. Shortly, David will elaborate more detail on the landmark data and next steps for this program. Beyond the NTLA 20-reed out, NTLA 2002, or in vivo knockout candidate for hereditary angio edema or HAE, and NTLA 5001, or lead engineer TCR, T-Cell Therapy for acute myeloid leukemia or AML, continue marching towards, In June, we shared that we submitted our first CTA for NTLA 2002 to regulatory authorities, and we're pleased to announce this morning that we have submitted our first CTA for NTLA 5001 as well.

More broadly we believe these results opening a new era in medicine, and what's occurring genetic disease made me within reach shortly David will elaborate more detail on the landmark data and next steps for this program.

Beyond the until a 'twenty 1 readout until late 'twenty 2 our in vivo knockout candidate for hereditary angioedema or H E and NPL, a 50 or 1 our lead engineered TCR T cell therapy for acute myeloid leukemia or AML continue marching towards the clinic.

In June we shared that we submitted our first Cta for until late 'twenty 2 to regulatory authorities and we're pleased to announce this morning that we have submitted our first Cta for <unk> 51, as well pending.

John M. Leonard: Pending regulatory authorization, both first in human trials are on track to begin by the end of this year. In addition, together with Cell Excel professional, in Blackstone life science, we launched a new Universal Car Tea Company, This new company combines Entelia's allogenetic cell engineering platform with a clinically validated universal CART construct from JMOA. Additionally, this company, which aims to develop differentiated immunoncology and autoimmune therapy, is resourced with up to a $250 million financing commitment from Black, In exchange for a license to our technology, Intelia will receive a significant equity stake of this new company, along with two options to co-develop and co-commercialized, two elegenic universal CARTE candidates in the U.S. and key European companies, collaborations like this are a key instrument of our broader corporate strategy to enable us to realize the full scope and potential of our technology for patients.

Pending regulatory authorization, both first in human trials are on track to begin by the end of this year.

In addition, together with Selic sales professionals and Blackstone Life Sciences, we launched a new Universal car T Company. This new company combined from <unk> Allogeneic cell engineering platform with a clinically validated universal car T construct from GMO App <unk>.

Additionally, this company, which aims to develop differentiated immuno oncology and autoimmune therapies is resourced with up to a $250 million financing commitment from Blackstone.

In exchange for a license to our technology until you.

Receive a significant equity stake of this new company, along with 2 options to co develop and co commercialize to allo generic Universal car T candidates in the U S and key European countries.

Collaborations like this 1 are a key instruments of our broader corporate strategy to enable us to realize the full scope and potential of our technology for patients that can extend the reach of our technology beyond our core areas of strategic focus while retaining rights across a diverse ex vivo landscape.

John M. Leonard: They can extend the reach of our technology beyond our core areas of strategic focus or retain rights across a diverse ex-veval landscape. And this collaboration brings the additional benefit of a concurrent manufacturing agreement with Seleks, which Laura will expand on a bit later. Finally, before passing the call on, I'd like to extend a warm welcome to two new members of our leadership team, Jim Basta, Executive Vice President and General Counsel, and Ian Carp, Senior Vice President of Investor Relations and Corporate Communications.

And this collaboration brings the additional benefit of a tongue current manufacturing agreement with <unk>, which Laura will expand on a bit later.

Finally, before passing the call on I'd like to extend a warm welcome 2 new members of our leadership team, Jim <unk> Executive Vice President and General Counsel and Ian Karp Senior Vice President of Investor Relations and corporate Communications, we're thrilled to have them join until yet and I have no doubt that our expertise and support will prove.

John M. Leonard: We're thrilled to have them join Intelia, and I have no doubt their expertise and support will prove to be of great value as our company continues to mature. I'll now hand over the call to our chief medical officer, David Leblow, who will recap our NTLA 21 data and provide a more in-depth update on our progress in the clinic.

To be a great value as our company continues to mature.

I'll now hand over the call to our Chief Medical Officer, David Lebel, who will recap or until late 'twenty, 1 data and provide a more in depth update on our progress in the clinic David.

Thank you John I'll start with a bit of background on ATT amyloidosis, and our approach with 'twenty 1.

David Neil Lebowitz: Thank you, John. I'll start with a bit of background on ATTR, Moy Dosis, and our approach with 2001. ATTR emloidosis is a rare and fatal disease caused by the buildup of TTR proteins in multiple organs. People living with the disease can have either the hereditary or wild type form, resulting in a diverse range of disease manifestations, the most frequent being polyneuropathy and cardio

GTR amyloidosis is a rare progressive fatal disease caused by the buildup of PTR protein in multiple organs.

People living with the disease can have either the hereditary or wild type form, resulting in a diverse range of disease manifestation, the most frequent being polyneuropathy and cardiomyopathy.

Our lead candidate 'twenty on 1 is the first systemically delivered CRISPR based therapy dosing a patient <unk>.

David Neil Lebowitz: Our lead candidate, 201, is the first systemically delivered CRISPR-based therapy dosed in a patient and a potentially curative treatment for ATTTR Amelodose. 201 applies our in vivo LMP delivery technology to knock out the TTR gene in the liver, which is a source of circulating TTR protein, therefore permanently reducing amyloid deposition after a single dose. Although the current standard of care has achieved meaningful therapeutic impact with roughly 80% knockdown of serum TPR, there remains unmet medical need in this population.

And a potentially curative treatment for <unk> amyloidosis.

101 applies our in vivo LNP delivery technology to knock out the TCR gene in the liver, which is a source of circulating <unk> protein, therefore permanently reducing amyloid deposition after a single dose.

Although the current standard of care has achieved meaningful therapeutic impact with roughly 80% knockdown of serum GTR there remains unmet medical need in this population.

David Neil Lebowitz: Moreover, as Dr. Gilmore shared at our June investor event, beyond the benefits of a one-time treatment, As demonstrated in ATPR, as well as other types of amyodosis, greater TTR knockdown is anticipated to improve clinical outcomes. We therefore believe a single-dose therapy that most importantly produces greater and durable TTR reduction will offer a significant benefit to patients and value to our health care system over the current standard of care. The 2021 Peripheral Neuro Society's annual meeting, and concurrently published in the New England Journal of Medicine, we shared positive interim data from a phase one study evaluating 201 in patients living with hereditary ATPR, MOA Dosis with polyneuropathy that support this hypothesis, data representing six patients from the first two dose courts of part one of the study, the single ascending dose portion, were highly encouraged showing that 201 induced a dose-dependent reduction in serum TTR.

Moreover, as Dr. Gilmore shared at our June Investor event.

On the benefits of a 1 time treatment.

As demonstrated in <unk> amyloidosis, as well as other types of amyloidosis Greater T. T. R. Knockdown is anticipated to improve clinical outcomes.

We therefore believe a single dose therapy that most importantly produces greater and durable GTR reduction will offer a significant benefit to patients and value to our health care system over the current standard of care.

The 2021 peripheral nerve society annual meeting and concurrently published in the New England Journal of Medicine, we shared positive interim data from our phase 1 study evaluating 21 in patients living with hereditary <unk> amyloidosis with Polyneuropathy that.

Support this hypothesis.

Data representing 6 patients from the first 2 dose cohorts of <unk>.

1 of the study with single ascending dose portion were highly encouraging share.

That 21 induced a dose dependent reduction in serum ctr.

In our second dose level 0.3 milligrams per kilogram, we achieved an average ctr reduction of 87% at day 28, reaching a maximum ctr reduction of 96%.

David Neil Lebowitz: In our second dose level, 0.3 milligrams per kilogram, we achieved an average TTR reduction of 87% at day 28, reaching a maximum TTR reduction of 96%. 2001 was generally well tolerated at both doses, with adverse events all being grade one and mostly unrelated to the treatment. Altogether, the data suggest that we can achieve targeted in vivo editing for the desired pharmacological effect, supporting 21 as a first-in-class, single-dose treatment for ATTR amyloidosis, validating our L&T technology, and unlocking treatment of diseases that originate in the liver.

101 was generally well tolerated at both doses with adverse events, all being grade, 1 and mostly unrelated to the treatment.

Altogether. The data suggests that we can achieve targeted in vivo editing for the desired pharmacological effect supporting 21 is a first in class single dose treatment for <unk> amyloidosis, validating our LNP technology and.

Unlocking treatment of diseases that originate in the liver.

In terms of next steps for this program, we are continuing enrollment in the dose escalation portion of the phase 1 study.

David Neil Lebowitz: In terms of next steps for this program, we are continuing enrollment in the dose escalation portion of the Phase 1 study. We plan to present additional data from part one of the study at a scientific or medical conference later this year, including additional durability data beyond 28 days from the initial cohort. For cohort three, each subject will receive a single dose of 20-at-1 at one milligram per kilogram.

We plan to provide additional data from part 1 of the study at a scientific or medical conference later this year, including additional durability data beyond 28 days from the initial cohort.

For cohort 3 each subject will receive a single dose of 21 at 1 milligram per kilogram.

David Neil Lebowitz: For cohort four, we have flexibility in the protocol to proceed to a higher dose or explore an intermediate. Once we identify the recommended dose, we plan to initiate part two of the trial, a single dose expansion trial. In this portion of the study, eight patients will be administered the recommended dose identified in part one, with the objective to further characterize the activity of 201, including an initial assessment of clinical measures of neuropathy and neurologic function. We expect to advance into part two of the study later this year.

For cohort 4 we have flexibility on the protocol to proceed to a higher dose we're exploring intermediate dose.

Once we identify the recommended dose we plan to initiate part 2 of the trial a single dose expansion cohort.

In this portion of the study 8 patients will be administered the recommended dose identified in part 1 with the objective to further characterize the activity of 21, including an initial assessment on clinical measures of neuropathy and neurologic function.

We expect to advance into part 2 of the study later this year.

In addition, we <unk>.

David Neil Lebowitz: In addition, we plan to engage with regulators, including the FDA, to move into later phase clinical trials in which we aim to include both patients with polyneopathy and cardiomyopathy. While we recognize these are interim phase one results, with much more to learn, observations so far are quite meaningful, offering support that substantially de-res Resists our in-in-in-in-in-in-in-in-in-in-in-in-in With that, I'll now turn over the call to our chief scientific officer, Lara Seploranito, to provide updates on our two additional development candidates, 2002 and 5001, and across our R&D. Thanks, David.

Plan to engage with regulators, including the F D. A to move into later phase clinical trials in which we aim to include both patients with Polyneuropathy and cardiomyopathy.

While we recognize these are interim phase 1 results with much more to learn observations. So far are quite meaningful offering support that substantially derisked our in vivo efforts.

We look forward to keeping you updated on our progress.

With that I'll now turn over the call to our Chief Scientific Officer, Laura Sepp Lauren Vito to provide updates on our 2 additional development candidates 20.

<unk> and <unk> and across our R&D effort.

Thanks, David.

David Neil Lebowitz: Given the modularity of our platform, we're equally excited about what the interim clinical data imply for our efforts beyond NTLA201. Now that we have demonstrated we can deliver to hepatocytes in humans, we believe this accelerates additional in vivo programs and increases their probability of technical success. This applies to several programs, and especially to our in vivo knockout programs, such as NTLA 2002, our wholly-owned candidate in development for HAE. NTLA 202 leverages the same LMP delivery system as NTLA 2001, but targets the KLKB1 gene in the liver to permanently reduce plasma calicran protein and thereby its activity, a key mediator of the disease. This approach is expected to provide continuous suppression of calicron activity and eliminate HAE attacks.

Given the modularity on how our platform we're equally excited about what the interim clinical data in July for our efforts be on N. DNA 21 now.

Now that we have demonstrated we can deliver to hit at the sites and Siemens. We believe this accelerates the development of validation on illegal programs and increases the probability of technical success.

These are based on several continents, and especially to other indeed on no cut programs such as LDL late 'twenty 2.

We're wholly on accommodate and momentum.

H E.

<unk> Leverages the same LNP delivery system as India late 'twenty, 1 targets, Nick Teo, Jamie 1 gene in the liver to permanently reduce plasma calico on protein and thereby creating a community acre finishes.

This approach is expected to provide continued suppression of Kelly connectivity and eliminate <unk>. Thanks.

In June alongside with Charles from NPL on 'twenty, 1 we announced the submission of our first clinical trial application to the New Zealand medicines and medical devices safety I'm, sorry day to initiate a first in human study for MTN late 'twenty 2.

Laura Sepp: In June, alongside results from NTLA 201, we announced the submission of our first clinical trial application to the New Zealand Medicines and Medical Devices Safety Authority to initiate a first Inhuman study for NTLA 2002. We're submitting additional applications for this program and expect to enroll the first patients by year end. The first in human study will evaluate NTLA 202 for safety, tolerability, and activity, including levels of calico and knocka in patients with HAE.

With additional applications for this program and expect on grow the first patients by year end.

The first in human study will evaluate Indian a 'twenty 2 for safety tolerability and activity, including levels of Calix knock on.

In patients with <unk>.

This program has leverage insights from MCA late 'twenty, 1 from its inception throughout its development and on the basis of our preclinical data and clinical results from MBNA 'twenty..1 we expect to determine the recommended dose with a very limited number of from dosing cohorts.

Laura Sepp: This program has leveraged insights from NTLA 2001 from its inception throughout its development, and on the basis of our preclinical data and clinical results from NTLA 21, we expect to determine the recommended dose with a very limited number of dosing cohorts. Now turning to our ex-vibbo F- Here we're using CRISPRK as a tool to create engineers out there.

Now turning to our ex vivo efforts.

And what are you seeing CRISPR Cas 9 as a tool to create engineered cell therapies.

Laura Sepp: Similar to our efforts in vivo, our proprietary approach to cell engineering serves as a foundation for our modular platform. This approach allows us to mix and match cell types targeting any modality and the edits necessary for eliciting the desired pharmacology. Regardless of therapeutic format, we expect to achieve highly efficient, sequential editing, high yields, optimal performance, and scalable manufacturing. Our lead program, NTLA 501, is a potential best in class engineered T cell therapy designed to treat all genetic subtypes of AML. This investigation candidate is an autolobos T-cell receptor or T-CR, T-cell therapy targeting the Wilm's T-Tumor 1 antigen and restricted to the HLA-A-O-2-1 allele.

Similar to our efforts in vivo our proprietary approach to Sunny engineering serves as a foundation to our modular platform.

This approach allows us to make some much sounds like targeting modality and it's necessary for at least 15 day beside of pharmacology.

Regardless of therapeutic format, we expect to achieve high efficient sequentially anything high yields on the commercial performance and scalable manufacturing.

Our lead program <unk>, 1 is a potential best in class engineered T cell therapy beside to trade all genetic subtypes of <unk>.

This investigation on the candidate Ethan Autologous T cell receptor or TCR T cell therapy that he gets.

The wilms tumor 1 antigen.

Restricted to the HLA a 2.1 on Neal.

Importantly, WT 1 is over expressed in more than 90% of AML patients regardless of mutation subtype.

Laura Sepp: Importantly, WT1 is overexpressed in more than 90% of AML patients regardless of mutational subtype, and HLA, A2, is one of the most common search terms. Furthermore, NTLA 51 utilizes our proprietary cell engineering process to replace patients' endogenous TCRs with the WT1 targeting TCR, creating a homogeneous cell product with high intrinsic potency and improved safety by eliminating TCR mispairing. By utilizing our sequential editing process, the result in the final product has the desired attributes of high viability, robust levels of expansion, desirable memory phenotype, increased functional activity, and reduced translocations.

And HLA <unk> hundred 1 each 1 of the most common share price.

Furthermore, installations day, 1 utilizes our proprietary and process to replace patients endogenous TCR weighted that'd be a day 1 tiger teams you see are creating a homogeneous cell product with high intrinsic potency and safety by eliminating TCR genes sparing.

By utilizing our sequential editing process that we sold came from products has the desired attributes high viability robust levels of expansion decides on memory phenotype increased functional activity and video strength locations.

Despite gross total therapeutic advances delivering improved response rates in subsets of AML.

Laura Sepp: Despite recent therapeutic advances delivering improved response rates in subsets of AML, long-term outcomes continue to be poor, with overall five-year survival below 30%. With our proprietary cell engineering process and the prevalence of WT1, we believe NTLA 501 will be a highly active and well tolerated agent to improve outcomes for A&L patients. As John mentioned today, we're excited to share that we have submitted our first CTA to the United Kingdom's Medicine and Healthcare Products Regulatory Agency for a phase one study of NTLA 501 in the United Kingdom.

On term outcomes continue to be poor with overall survival below 30%.

We have a proprietary cell engineering processes on the prevalence of navigate to 1 we believe LDL AC tier 1 maybe a highly active and well tolerated agent team proved outcomes for AML patients.

John mentioned today, we're excited to share that we have submitted our first CPA cause the United Kingdom's may be seen on healthcare products regulatory Agency force Phase 1 study of N T. L. A 51 in the United Kingdom.

This first inhuman trial will evaluate the safety and activity of Mpls 50, and 1 in patients with persistent or recurrent AML, who had previously received first line therapies.

Laura Sepp: This first in-human trial will evaluate the safety and activity of NTLA 51 in patients with persistent or recurrent AML who have previously received first-line therapy; we expect to be screening patients for the phase one study by the near end.

We expect to be screening patients for the phase 1 study by year end.

Beyond Ngls 51, we plan to share more information on our electronic submission later this year. We believe our approach is differentiated from others. Currently in the clinic that typically address poorly graft versus host rejection.

Laura Sepp: Beyond NTLF 51, we plan to share more information on our Alpenaic solution later this year. We believe our approach is differentiated from others currently in the clinic that typically address only Graf versus Hose disease. We have focused on creating allogenic cells that not only avoid Graf versus Hose disease but also persist by avoiding elimination by host T cells and NK cells.

We have focused on creating allogeneic cells that not totally avoid graft versus host disease, but also persist.

Boyd in elimination by host T cells and NK cells.

Laura Sepp: This approach should avoid the aggressive lymphal depletion and the reduced profound immunodeficiency currently employed to address a significant challenge in adopted cell therapy. In June, to launch a new Universal CARE cell therapy company, we entered into a preferred partnership agreement with SELEC. This agreement provides Intelia access to dedicated GMP manufacturing capacity and high-quality donor cells for our allogenic programs. Our access to both will be of great value in supporting and accelerating the development of our wholly-owned Exvibo program.

This approach should avoid the aggressive inc. For depletion and reduce funding efficiency current employed to address a significant challenge in adoptive cell therapy.

In June concurrent to launching a new Universal car T cell therapy company, we entered into a preferred partnership agreement with <unk>.

This agreement provides italia access to dedicated GMP manufacturing capacity and high quality done ourselves for our allogeneic brokerage.

Our access to both will be of great volume is supporting and accelerating the development of our wholly owned ex vivo programs.

All the R&D progress along with demonstrations earlier this year such as preclinical data in from using our proprietary <unk> based editor and our first demonstration of in vivo editing.

Glenn G. Goddard: All the R&D progress, along with demonstrations earlier this year, such as preclinical data, introducing our proprietary base editor, and our first demonstration of in vivo editing outside the lever, reflects both the breadth of our technologies' reach and our steadfast commitment to drive our pipeline forward through continued platform innovation. To that end, we plan to present additional in-bibble and ex-bibble updates at scientific conferences later this year. We remain on track to nominate at least one new development candidate this year, and we continue to work towards nominating the company's first allogenic development candidate by the first half of 2022.

<unk> outside the liver reflects both the breadth of our technology suite and our steadfast commitment to drive our pipeline forward to the continued platform innovation. So.

To that end with tens of percent addition on in vivo and ex vivo update per se different conferences later this year weighted.

We remain on track to nominate at least 1 new development candidate this year and we continue to work towards nominating the company's first allogeneic development candidate by the first half of 2022.

Glenn G. Goddard: With that, I would like to hand over the call to our CFO, Glenn Goddard, who will provide an overview of our second quarter financial results. Thank you, Lauren. Our cash, cash equivalents, and marketable securities were $551.

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

Thank you Laura and good morning.

Our cash cash equivalents in marketable securities.

$551.3 million as of June 32021.

Glenn G. Goddard: $551. As of June 30, 2021, compared to $597 as of December 31, December 31. The decrease was driven by cash used to fund operations of approximately $115, which was offset in part by $45.3 million of net proceeds from the companies at the market, $20.5 billion in proceeds from employee-based stock, and $3.2 million of funding from cost sharing agreements with Regenerals. Following the disclosure of our NTLA 2201 clinical data, we completed the successful follow-on offering in July, raising $648, putting us and tell you in a strong position to aggressively advance and expand our pipeline. However, our collaboration revenue decreased by $9.7 million to $6.

Compared to $597.4 million.

December 31.2020.

The decrease was driven by cash used to fund operations of approximately $115.1 million.

Which was offset in part by $45.3 million of net proceeds from the company's at the market agreement $20.5 million and proceeds from employee based stock plans and $3.2 million of funding from cost sharing agreements with regeneron.

Following the disclosure of our <unk> to 'twenty on 1 clinical data we completed a successful follow on offering in July raising.

Raising $648.1 million in net proceeds.

But I can tell you in a strong position to aggressively advance and expand our pipeline.

Our collaboration revenue decreased by $9.7 million to $6.6 million during the second quarter of 2021 compared to $16.3 million during the second quarter of 2020.

Glenn G. Goddard: During the second quarter of 2021, compared to $16.3 million during the second quarter of 2020, the decrease was driven by $8.4 million of revenue recognized for a one-time catch-up adjustment related to the amendment and expansion of our 2016 Regeneron Collaboration Agreement in Q2 of last year. Our R&D expenses increased by $21.1 million to $58. During the second quarter of 2021, compared to $37.8 million during the second quarter of 2021 compared to $37.8 million during the second quarter of 2020.

The decrease was driven by $8.4 million of revenue recognized for onetime catch up adjustment related to the amendment and expansion of our 2016 Regeneron collaboration agreement in Q2 of last year.

Our R&D expenses increased by $21.1 million to $58.9 million during the second quarter of 2021 compared to $37.8 million.

During the second quarter of 2020.

Glenn G. Goddard: This increase was driven by a $10 million one-time payment related to the amendment of our 2014 Novartis Agreement, as well as employee-related expenses due to the continued expansion of our development organization. Our GNA expenses increased by $5.2 million to $16.7 million during the second quarter of 2020, compared to $11.5 million during the second quarter of 2020. This increase was mainly due to employee-related expenses, including stock-based compensation of $2.1 million.

This increase was driven by a $10 million of 1 time payment related to the amendment of our 2014 Novartis agreement as well as employee related expenses due to the continued expansion of our development organization.

Our G&A expenses increased by $5.2 million to $16.7 million during the second quarter of 2021 compared to $11.5 million during the second quarter of 2020.

This increase was mainly due to employee related expenses, including stock based compensation of $2.1 million.

John M. Leonard: And finally, we expect our current cash balance to fund our operating plans beyond the next 24 months, as Intelia is well positioned to drive long-term growth and execute on our upcoming miles. And now, I will turn the call back over to John for his closing remarks. Thank you, Glenn. As you can see, we've made significant progress executing against the ambitious goals and strategic priorities set forth at the beginning. A presentation of proof-of-concept clinical data from the first ever study of a systemically administered CRISPR Genome editing therapy in humans was clearly a high-line. Not only is this data important for the ATTR amyosis community, but it helps us advance our growing full-spectrum, Moreover, this milestone represents just one key step in unlocking the full therapeutic potential of our CRISPR platform.

And finally, we expect our current cash balance to fund our operating plans beyond the next 24 months as I'm, telling you is well positioned to drive long term growth and execute on our upcoming milestones.

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

Thank you Glenn.

As you can see we've made significant progress executing against the ambitious goals and strategic priorities set forth at the beginning of this year.

A presentation of proof of concept clinical data from the first ever study of a systemically administered CRISPR genome editing therapy in humans was clearly a highlight.

Not only is this data are important for the ATT amyloidosis community, but it helps us advance our growing full spectrum pipeline.

Moreover, this milestone represents just 1 key step in unlocking the full therapeutic potential of our CRISPR platform.

Following the positive interim data from our phase 1 study of until late 'twenty..1 we'll look forward to sharing additional interim results and to initiate part 2 of the study a single dose expansion cohort later this year.

John M. Leonard: Following the positive interim data from our phase one study of NTA 2001, we look forward to sharing additional interim, into initiating part two of the study of single dose expansion cohort later this year. We continue to progress our pipeline with CTA submissions for our second in vivo candidate, NTLA 2002, and our lead ex-Vivo candidate, NTLA 5001, and we anticipate initiating both First and Human Trials by the end of the, With validation of our CRISPR Cast9 platform, we remain on track to nominate at least one new development candidate by the end of Additionally, we plan the share pre-clinical data on our Allogenic solution this year and expect to nominate the company's first allogenic development, by the first half of the next year.

With continued to progress our pipeline with Cta submissions for a second in vivo candidate until late 'twenty, 2 and our lead ex vivo candidate until 851, and we anticipate initiating both first in human trials by the end of this year.

With validation of our CRISPR Cas line platform, we remain on track to nominate at least 1 new development candidate by the end of the year. Additionally, we plan to share preclinical data on our allogeneic solution. This year and expect to nominate the Companys first allogeneic development candidate by the first half of next year.

And across our R&D efforts, we look forward to sharing additional in vivo and ex vivo updates at upcoming scientific and medical conferences.

We're eager to carry this momentum forward as our recent progress offers a springboard from which to advance our long term vision for <unk>.

Operator, you May now open the call for questions.

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

To ask a question you May Press Star then 1 on your Touchtone phone.

If youre using a speakerphone please pick up your handset before pressing the keys to withdraw your question. Please press Star then 2.

John M. Leonard: And across our R&D efforts, we look forward to sharing additional in vivo and ex-vivo updates at upcoming scientific and medical meetings. We are eager to carry this momentum forward as our recent progress offers a springboard from which to advance our long-term vision for operator, you may now open the call for Thank you. We will now begin the question and answer session. Taffly question, you may press star, then one on your touchtone phone.

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

Our first question comes from Maury Raycroft from Jefferies. Please go ahead.

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

To start off I was wondering if you can talk more about when you aimed to engage with FDA about next step trials would that be after the 8 patient expansion data or can you have those meeting sooner and for the 8 patient expansion any new thoughts on on how many mixed patients will be included in that and if you will.

We will assess for cardiovascular measures and biomarkers like empty pro BNP.

Operator: If you're using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. At this time, we'll pause momentarily to assemble our roster. Our first question comes from Mari Raycroft of Jeffreys. Please go ahead. Hi, good morning everyone, congrats on the progress and thanks for taking my questions. To start off, I was wondering if you could talk more about when you aim to engage with FDA about Next Step trials.

Thanks, Lori good morning, nice to hear from you maybe I'll start with David David can just tell us a little bit about your plans for a progression that work.

Thank you John Thank you more so with the data that we have from the phase 1 so far we're seeing that we've achieved 87% reduction in Q T. R. So this result is as you know is better than what's available therapies in the trial. We think we are getting close to where we need to do with dosing we will be.

Reporting on that.

Before the end of the year.

We are at the same time planning on the next studies at this time, we don't think we need any particular additional data to be able to engage with regulators both the FDA and other regulators around the world about our next crowds.

Operator: Would that be after the eight patient expansion data, or can you have those meetings sooner? And for the eight patient expansion, any new thoughts on how many mixed patients will be included in that? And if you will assess for cardiovascular measures and biomarkers like NP probiant? Thanks, Maury. Morning. Nice to hear from you. Maybe I'll turn to David.

In terms of the expansion what what is in the trial is described as patients with Polyneuropathy.

If you look in clinical trials that we talked about some of the measures. There are measures of cardiac function because as you know many of these patients do as well have cardiac involvement, but they don't have heart failure remains involvement is neuropathy.

John M. Leonard: David can just tell us a little bit about your plans for progressing the work. Yeah, thank you, John. So with the data that we have from phase one so far, we're seeing that we've achieved an 87% reduction in TTR. So this result is, as you know, better than what's available with available therapy. So in the trial, we think we are getting close to where we need to be with the dose. We will be reporting on that before the end of the year.

Got it that's all helpful and so it sounds like you could potentially engage with with our.

Regulators sooner than later to get some additional feedback on what next step trials could look like.

Got it and that is a reasonable assumption.

Okay.

And then follow up question just on our cohort 4 what are gating factors to determine if you decided to SaaS in the intermediate dose at dose level in that cohort and what could that dose looked like.

John M. Leonard: We are at the same time planning for the next studies at this time. We don't think we need any particular additional data to be able to engage with regulators, both the FDA and other regulators around the world, about our next plan. Um, in terms of the expansion, what is in the trial is described as patients with polyneuropathy. We, if you look at Clinical Trials.gov, we talk about some of the measures. There are measures of cardiac function because, as you know, many of these patients also have cardiac involvement, but they don't have heart failure. Their main involvement is neurophicine.

Yeah, we're going to look at the data from cohort 3 we mentioned cohort 4 but it's not required within the study. If we think we have the right dose to go forward based on the first 3 doses. We can do that but we also do have the flexibility to go to either an intermediate dose the tire on.

Lower than that 1 milligram per kilogram. So we'll be looking at all the data that comes in a free.

From the third cohort.

And then decide what to do after that.

Okay makes sense, thanks for taking my questions on Opex in the queue.

Thanks.

The next question comes from <unk> Richter from Goldman Sachs. Please go ahead.

Hi, Thank you so much for taking our question. This is sonya on for Celgene.

David Neil Lebowitz: Got it. That's all helpful. So it sounds like you could potentially engage with regulators sooner than later to get some additional feedback on what next step trials could look like. That is a reasonable assumption.

2 questions on the first is on and telling you to on 1.

How should we think about the upcoming data for cohort 3 and 4.

Just if you could help us frame expectations, there and then the second 1 is on the.

The trial design for WTO on ammo on just if you could remind us what that is again that would be helpful. Thank you.

I think I'll turn to David again a.

David Neil Lebowitz: Okay. And then follow-up question just on a cohort: what are the dating factors to determine if you decide to assess an intermediate dose at a dose level in that cohort, and what could that dose look like? Yeah, we're going to look at the data from cohort three. We mentioned cohort four, but it's not required within the study. If we think we've got the right dose to go forward based on the first three doses, we can do that.

That'd be just say a little bit about or.

Our expectations for the end of the year and I know, it's early for W. T..1 trial designs, but Nathan just speak to where we are on the regulatory process just remind our listeners.

Okay, well thank you John.

So what we'll be reporting before the end of the year is additional data from the dose escalation portion of the trial.

So from our reported so far is that we will have data from patients receiving 1 milligram per kilogram.

David Neil Lebowitz: But we also do have the flexibility to go to either an intermediate dose that's higher or lower than that one milligram per kilogram. So we'll be looking at all the data that comes in from the third cohort and then decide what to do afterward. Okay, thanks for taking my questions, and I'll hop back in the queue. The next question comes from Salveen Richter from Goldman Sachs. Please go ahead. Hi, thank you so much for taking our question. This is Sonia on for Salve.

And we've also said that we'll be talking more about the durability and the cohort the existing patients on the trial.

Of course, we'll bring forward as much information as we can from the trial and in and let people know where we are with that.

Looking at <unk>, 1 we we have announced that we made our first cta submission or a regulatory submission matters.

And with that we will we will be talking about the trial design. After we are really getting started with the trial. We have 2 we have our first approval to move forward in the trial.

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

Hi, Thank you Sheldon on for Keith.

Thank you for taking our question.

We have 2.1 on <unk>.

John M. Leonard: We just had two questions. The first is on Antelia 201. How should we think about the upcoming data for cohorts 3 and 4? Could help us frame expectations there. And then the second one is on the trial design for WT1 AML. Just if you could remind us what that is again, that would be helpful. I think I'll turn to David again.

On the old 1 so for the second half update.

But narrow it down a little bit for us.

On whether its third quarter or fourth quarter, and how could you update us on I saw on the enrollment progress.

Yes. This is John Thanks Sheldon.

We're really not going to be able to give more specificity other than we'll give you an update by the end of the year and we will apply the principles that we've been applying throughout the study to date.

David Neil Lebowitz: David, just say a little bit about our expectations for the end of the year. And I know it's early for WT1 trial designs, but they can just speak to where we are in the regulatory process, just remind our listeners. Okay, thank you, John. So, what we'll be reporting before the end of the year is additional data from the dose escalation portion of the trial. What you know from our report so far is that we will have data from patients receiving one milligram per kilogram.

We want those updates to be interpretable meaningful and consistent and that's been what's been guiding us on throughout.

Throughout the work so.

You know, it's certainly our expectation to share more information, but.

David Neil Lebowitz: And we've also said that we'll be talking more about durability in the cohort and existing patients in the trial. Of course, we'll bring forward as much information as we can from the trial and let people know where we are. Looking at 50, we have announced that we've made our first CTA submission or regulatory submission, and with that, we will be talking about the trial design after we are really getting started with the trial after we have our first approval to move forward in the trial. The next question comes from Gina Wong from Barclays. Hi, this is Sheldon now for Tina.

John M. Leonard: Thank you for taking our request. We have to one for 2001. So for the second half updates, could you narrow it down a little bit for us, whether it's third quarter or fourth quarter, and I'll update us also on the enrollment program. Yeah, this is John.

John M. Leonard: Sheldon, we're really not going to be able to give you any more specifics other than we'll give you an update by the end of the year. And, you know, we will apply the principles that we've been applying throughout the study today. We want those updates to be interpretable, meaningful, and consistent, and that's been what's been guiding us throughout the work. So, you know, it's certainly our expectation to share more information, but as we did with the first go around, we'll give people advance notice on where we're going to do that and how we're going to do that. So stay tuned for that. We're not going to surprise anybody by this.

Very much a function of the protocol design and the rate of progression of enrollment that dictates. What you can talk about so stay tuned again I you know I I think you should just expect that will do it in a fashion is quite similar to what we did with 21.

That's very helpful. Thank you.

The next question comes from June Lee from True Securities. Please go ahead.

Hi, Thanks for taking a question from yesterday.

John M. Leonard: Right, very helpful. My second question is about HAE. So when you show, share the data, how should we think about the dating factors, about when you will be able to share, it's like to achieve certain follow-up or to achieve certain lockdown levels. Yeah, I think that's premature at this time. I understand what's behind the question. You know, we've begun the regulatory process as we laid out, and we're excited about moving that forward very, very expeditiously.

And the court 1 if you look at the day that day didn't look like they play code have you collected more data beyond day 28, and if so as you see further knock down and T. T R and related to that you know when will you be able to share with clinical day, which could be particularly interesting given the completely different.

P. K P D profile compared to S O and I have a follow up.

I'll I'll take that you know David said in his comments will provide more information as the study progresses and we've committed to doing that before the end of this year. We presented the day to that we had [laughter] you know, it's an ongoing study and.

John M. Leonard: As Laura commented, you know, we think we're in a very good position to benefit from the work that's been done with 50-01, and that will find its way into the clinical program. Once we've cleared on the regulatory side, we'll talk about the specifics of the program and the protocol.

John M. Leonard: And at that point, we can start to think ahead about what we'll share and when we'll share it. But I think, as you know, in these first human studies, it's all very much a function of the protocol design and the rate of progression of enrollment that dictates what you can talk about. So stay tuned again. You know, I think you should just expect that we'll do it in a fashion quite similar to what we did in 2011. That's very helpful.

What we tried to do is per cent information that we think is meaningful and generally speaking we expect the T. T. R effects too settle out by day, 28th but subsequent work in data collection I think will corroborate that at least based on preclinical work, but you know with the upcoming up.

Operator: The next question comes from June Lee from Truist Securities. Please go ahead. Hi, thanks for taking our questions and for the update. For the patients in cohort one, you know, if you look at the data, they didn't look like they plate-poded. Have you collected more data beyond day 28 and, if so, do you see a further knockdown in TTR?

They will share the information that we have so stay tuned you know, it's an ongoing process with respect to the clinical information that's something that will collect more robustly in the second stage of the study although there's some descriptive work in this first phase which is you know.

Operator: And related to that, you know, when will you be able to share some clinical updates, which could be particularly interesting given the completely different PKPD profile compared to ASO? And I have a follow-up question. I'll take that.

Will speak to the particular doses that the patients have received so as as we shared with our update a few weeks ago.

John M. Leonard: David said in his comments that we'll provide more information as the study progresses, and we've committed to doing that before the end of this year. We presented the data that we had. You know, it's an ongoing study, and what we tried to do is present information that we think is meaningful. And, generally speaking, we expect the TTR effects to settle out by date 28. But subsequent work and data collection, I think, will corroborate that, at least based on preclinical work. But, you know, with an upcoming update, we'll share the information that we have. So stay tuned.

Cohort 1 we think well yeah has very very meaningful knocked down but I don't think presents the drug with the maximum effect that 1 would hope to see from a clinical point of view, so that better more robust description really is gonna come on stage 2.

And then you know as you advance to talk on 1 towards commercialization can you discuss your freedom to operate in the U S. Specifically that you have to commercialize that and do you I'm income bird or do you foresee a need to negotiate with another company or per royalty is that something team spots that will be tackling. Thank you.

John M. Leonard: You know, it's an ongoing process. With respect to the clinical information, that's something that will be collected more robustly in the second stage of the study. Although there's some descriptive work in this first phase, which, as you know, will speak to the particular doses that the patients have received. So, as we shared with our update a few weeks ago, cohort one, we think, well, you know, has very, very meaningful knockdown but I don't think presents the drug with the maximum effect that one would hope to see from a clinical point of view.

Ya.

[laughter] I I I think we're in a really good position to commercialize the product and at this point.

Anything to share specifically with respect to dealings with other companies.

Thank you.

The next question comes from Luc E C from our a B C capital markets. Please go ahead.

Oh, great. Thanks, so much for taking my credit check congrats on on the progress here I have a total is ask a question on durability I'm on a gene therapies and imperfect comp, but we have C. B S. P. A asking for at least 2 years durability before considering approval at least for liver and you can look at it Biomarin date.

John M. Leonard: So that better, more robust description really is going to come to stage two. Got it. And then, you know, as you advance 2001 towards commercialization, can you discuss your freedom to operate in the U.S. specifically, you know, to commercialize that in the U.S., unencumbered, or do you foresee a need to negotiate with another company or paired royalty? Is that something James Bossa will be tackling

Mmm Ophelia, a as a cop.

Conceptually do you anticipate the F D. A to ask shorter timeline for a jeep heading give me his permanent in nature or maybe do expect them to asking a longer time line, we don't really understand longterm consequences of potential off target effects. Thanks, so much.

John M. Leonard: Thank you. I think we're in a really good position to commercialize the product and, at this point, anything to share specifically with respect to dealings with other companies? The next question comes from Luca EC from RBC Capital Markets. Please go ahead. Well, great.

[noise] that is not only philosophical but also speculative and [laughter] you know I I think.

Look on the spirit of your question the specifics of what's Gonna take for this particular therapy to be approved by regulators or something that will be subjected to you know I'm going in future regulatory studies I think that in the case of gene therapy in terms of how we view it.

John M. Leonard: Thanks so much for taking my question. Congratulations on all the progress here. I have a full Glasgow question on durability.

John M. Leonard: I know gene therapy is an imperfect comp, but we have seen the FDA asking for at least two years of durability before considering approval, at least for liver, and you need to look at the biomarin data in Emophilia A as a comp. Conceptually, do you anticipate the FDA to ask a shorter timeline for jeetting, given it's permanent in nature, or maybe do you expect them to ask an even longer timeline, given we don't really Thanks, That is not only philosophical but also speculative.

The particular approach has inherent tendencies to at least be susceptible to waning overtime and that's I think is is you know tied to the notion of having an episode that does not.

Integrated into the genetic material Michelle it's.

It's our expectation and we certainly share it a lot of preclinical work to support this that the effects should be in the case of gene editing lifelong over the you know like from of the patient and we have no evidence to the contrary at this point.

John M. Leonard: And, you know, I think, in the spirit of your question, the specifics of what it's going to take for this particular therapy to be approved by regulators is something that will be subjected to, you know, ongoing regulatory studies. I think that in the case of gene therapy, in terms of how we view it, the particular approach has inherent tendencies to at least be susceptible to waning over time. And that, I think, is, as you know, tied to the notion of having an episome that is not integrated into the genetic material of the cell.

So we'll see what the F. D. A is looking for but I think that certain principles that are analogous to gene therapy are likely to be applied but a lot of that is just looking for the clinical outcomes that come with it and sufficient information to indicate that assumptions are correct.

Alright, thanks, so much on.

The next question comes from many <unk> from S V D. Leer link. Please go ahead.

Good morning. This is Greco on farm Mani Thanks for taking my question.

John M. Leonard: It's our expectation, and we certainly have a lot of pre-clinical work to support this, that the effects should be, in the case of gene editing, lifelong for the life of the patient. And we have no evidence to the contrary at this point.

What is your current thinking around a regulatory path for on 20 on whining cardiomyopathy, and poly neuropathy Ah phenotype and die in context of existing treatment options like stabilisers in silence or something between O types and on and that are becoming standard of care are you guys expecting to do noninferiority.

John M. Leonard: So we'll see what the FDA is looking for, but I think that certain principles that are analogous to gene therapy are likely to be applied, but a lot of that is just looking for the clinical outcomes that come with it and sufficient information to indicate that the assumptions are correct. Thanks so much, John. The next question comes from Mani Foruhar from SVB; please go ahead. Good morning. This is Greco on for Mani.

<unk> you know types.

I I'd say at this time, it's far from a foregone conclusion that in the cardiomyopathy space in particular will be required to do comparative studies and obviously, we we watch the space carefully to learn whatever we can from the <unk>.

Egress from other agents I don't think that most kols would agree that there's a standard of care and certainly from a knockdown point of view, there's not even improved product yet for cardiomyopathy, so that basis of thinking I think for a regulatory size for us is probably.

John M. Leonard: Thanks for taking my questions. What is your current thinking around the regulatory path for 2001 in cardiomyopathy and polyneuropathy phenotypes in the context of existing treatment options like stabilizers and silencers and these phenotypes, which are becoming standard of care? Are you guys needing to do non-inferiority studies for one or both phenotypes? I'd say at this time it's far from a foregone conclusion that in the cardiomyopathy space, in particular, we will be required to do comparative studies, and obviously, we watch the space carefully to learn whatever we can from the progress of other agents. I don't think that most KOLs would agree that there's a standard of care, and certainly from a knockdown point of view, there's not even an improved product yet.

Quite premature so with respect to the Polyneuropathy space, that's worth that we're thinking through at this point.

But you know where the program stands today as we're especially interested in getting information and the cardiomyopathy patience and you know after David selection is optimal biological dose and we collect that information then we'll progress that does like efficiently as we can.

Often on my second question is that so so far we've seen H B day and from from from 3 different programs I think a T. T. R. H a N E T D, but that pet that doses aren't we're not disclose but in terms of knock on efficiency are you think similar knockout.

John M. Leonard: for cardiomyopathy. So that basis of thinking, I think, for regulatory studies for us, is probably quite premature. So with respect to the polyneuropathy space, that's work that we're thinking through at this point. But you know, where the program stands today, we're especially interested in getting information from the cardiomyopathy patients. After David selects his optimal biological dose and we collect that information, then we'll progress that as efficiently as we can. It was awesome.

Across different genes. That's another dose on hold or are you I seen some meaningful differences and knock on efficiency, depending on that gene of interest.

And how did that in combination.

Combination west on your on line clinical data informed about that child at 9 and knock on expectations for 20 O 2 and a K.

John M. Leonard: My second question is that so far, we've seen NHB data from three different programs, I think, ATTR, and H-A-E-N-A-A-T-D, but the tested doses are not disclosed. But in terms of knockout efficiency, are you seeing similar knockout across different genes at similar dose levels, or are you seeing some meaningful differences in knockout efficiency depending on the gene of interest? How does that affect that?

Well 1 of the benefits of the modular approach is that we use the same lipid show that contains essentially the same cargo.

And by that I mean, specifically the mrna that and codes to cast 9 [noise] enzyme and for that matter of the guide or in a is virtually identical with the exception of the last 20 nuclear tides.

John M. Leonard: Combining with 2001 clinical data, inform both the trial design and knockout expectations for 2002 in H.A. Well, one of the benefits of the modular approach is that we use the same lipid shell that contains essentially the same cargo. And by that, I mean specifically the MRNA that encodes the Cas9 enzyme.

What we've found is that from a product efficiency point of view on our preclinical models, there's a great consistency across all the different targets that we've pursued so we're excited that the logic that we employed at the very beginning about modularity.

John M. Leonard: And for that matter, the guide RNA is virtually identical with the exception of the last 20 nucleotides. What we found is that from a product efficiency point of view in our pre-clinical models, there is great consistency across all of the different targets that we've pursued. So we're excited that the logic that we employed at the very beginning about modularity appears to be holding true. And I think the first real test of that's going to be as we move to 2002, and hopefully, it will corroborate the results that we've already seen with 2001.

Here's to be Ah holding true and I think the first real test of that is gonna be as we move to 20 O 2.

And ideally hopefully corroborate the results that we've already seen with 20 O..1 but are are preclinical studies, which have been a very good guidance. Thus far is have been very very helpful. In terms of predicting where we go in humans.

Thank God really appreciate the detail on thanks again for taking my question.

The next question comes from J Olson from Oppenheimer. Please go ahead.

John M. Leonard: But our pre-clinical studies, which have been a very good guide thus far, have been very, very helpful in terms of predicting where we go in humans. Thanks. I really appreciate the detail and thanks again for taking my questions. The next question comes from Jay Olsen from Oppenheimer. Please go ahead.

Okay. Thank you for taking the questions maybe just to follow up on.

20, O 1 and cardiomyopathy myopathy do you think that the greater T. T. R knockdown can lead.

Lead to improved clinical benefits in in both cardiomyopathy and pulling Uropathy and then maybe just a quick question on 50 O..1 for N. L. Since you are planning to do your early clinical work in the UK can you remind us sort of the pros and cons.

John M. Leonard: Oh, okay, thank you for taking the questions. Maybe just to follow up on, uh, 20-201 in cardiomyopathy, do you think that a greater TTR knockdown can lead to improved clinical benefits in both cardiomyopathy and polyneuropathy? And then maybe just a quick question on 50-01 for AML. Since you're planning to do your early clinical work in the UK, can you remind us sort of the pros and cons of doing that work in the UK versus submitting an I&D in the U.S.

<unk>.

Doing that work in the UK versus submitting an I N D. A U S. Thank you.

[noise] [noise], let me speak to the the whole knockdown question on our central thesis.

And I think it's a ceaseless thesis that's broadly held in amyloidosis field is that you want to reduce the offending protein to the greatest extent possible and by that I mean to the greatest extent possible and there's a clinical evidence.

John M. Leonard: Thank you. Let me speak to the whole knockdown question. Our central thesis, and I think it's a thesis that's broadly held in the amylidosis field, is that you want to reduce the offending protein to the greatest extent, and by that, I mean to the greatest extent possible. And there's clinical evidence, you know, when you look broadly across different proteins that cause different forms of amyloidosis, to indicate that that's the case, and there's even existing clinical data for the agents that currently exist that suggest that deeper responses lead to better effects.

You know when you look broadly across different proteins that costs different forms of amyloidosis to indicate that that's the case and there's even existing clinical data for the agents that currently exists that suggest that deeper responses lead to better effects.

There's no reason that we can think of and no. Good reason that we'd heard and we certainly discussed this extensively with people who are experts from the field to indicate that that's gonna be any less true for cardiomyopathy than it is for <unk> poly neuropathy and so the goal of our program is 2.

John M. Leonard: There's no reason that we can think of and no good reason that we've heard, and we certainly discussed this extensively with people who are experts in the field, to indicate that that's going to be any less true for cardiomyopathy than it is for polyneropathy.

John M. Leonard: And so the goal of our program is to achieve those greatest responses and TTR that we possibly can. And we believe, you know, clinical trials then will bear that out. And that is, as I said, you know, the central thesis of the overall program. With respect to 50-20 or the TCR program, I would point out that regulatory submissions are in their early stages, and I would not view this as limited in any way and certainly not limited to the UK.

Achieve those greatest responses and T T R that we possibly can.

And we believe you know clinical trials and will there that out and that is as I said you know that's interest central thesis of the overall program.

With respect to 50 O 1 or the T. C R program.

I would point out that the regulatory submissions are in their early stages and I would not view this as limited in any way and certainly not limited to the U K. However, our experienced in the UK and we anticipate that will continue this way has been excellent with standards of care that.

John M. Leonard: However, our experience in the UK, and we anticipate that we'll continue this way, has been excellent, with standards of care that are essentially indistinguishable from those that would be expected here in the U.S. So from a limitation point of view, we don't see any. Great, thanks for taking the questions. The next question comes from Steve Seathouse from Raymond James. Hi, this is Ryan Deshner, I'm on behalf of

<unk> are essentially indistinguishable from those that would be expected here in the U S. So from a limitation point of view, we don't see any.

Great. Thanks for taking my questions.

Sure.

The next question comes from Steve Seedhouse from Raymond James. Please go ahead.

Hi, This is Ryan Deschner on for Steve Seedhouse. She wanted to ask you guys expect to report M. As plus 7 data on the a T. T. R trial by end of year.

John M. Leonard: She wanted to ask, do you guys expect to report MS Plus 7 data in the ATDR trial by the end of the year in patients at a clinically relevant dose and who have a follicle? David, the question is, do you expect any MNIS data from this trial by the end of the year? The, we are measuring M-MIS as part of the, you know, not M-NIS plus seven, as part of the, for early Of course, this is in dose escalation, so there'll be very limited follow-up.

Patients clinically relevant does not have a follow up question.

David The question is just do you expect any mnist data from this trial by the end of the year.

The you think we are measuring and this is part of the you know not in this for 7 as part of the the early patient of course this isn't gross escalation so there'll be very limited follow up.

True if if it were sufficient follow up to be meaningful we presented but we're not sure we will have that true.

John M. Leonard: So if the first sufficient follow-up is meaningful, we present it, but we're not sure we'll have that. Okay, thanks for that. And then also, have you, or do you plan to assess the 20-O1's propensity for Chromostripsis XVo, and is there a way to monitor this in-Vo? This work has been done extensively in the preclinical setting, and it has been characterized and even reported on with respect to any off-target analyses in the New England Journal paper.

Okay. Thanks for that and then also have you or do you plan to assess the 20th ones propensity for criminals trips. This ex vivo and is there a way to monitor this can be though.

[noise].

This work has been done extensively in the preclinical setting and that has been characterized and even reported on with respect to any off target analyses in the new England Journal pay per I refer you to the supplement where it's [laughter] far longer than the paper it's.

John M. Leonard: I refer you to the supplement, which is far longer than the paper itself. It speaks to how this work is done, the data that's resulting, and the testing at concentrations that far exceed those that are expected to be achieved in the clinic. And from the standpoint of chromothripsis, I don't think the word even applies, actually. What we're looking for is any evidence of off targets. And what we find is that there are none at the doses and concentrations that we are administering to patients.

Self speaks to how this work is done the data that's resulting they testing at concentrations that far exceed that those that are expect to be achieved in the clinic.

And from the standpoint of chroma Thrips us I don't think the word even applies actually [laughter]. What we're looking for is any evidence of off targets and what we find is that there are no on at the doses and concentration set where.

Administering to patients.

John M. Leonard: Okay, thank you very much. The next question comes from Sylvan Turkan from J&P. Please go ahead. Good morning, and thanks for taking my question. I have two questions, please. Just on the Tellier 501 trial. I know you can't tell us much about the trial, but would there be any reason to believe that there would be major differences from the Fred Hutchison trial that, you know, included pre- and post-transplant patients? Would there be any reason why you would exclude one of them or not?

Okay. Thank you very much.

The next question comes from Sylvan, Turkey from JMP. Please go ahead.

Hi, Good morning, Thanks for taking my question I have 2 questions. Please just on the and and how you're at 50 O..1 I know you can't tell us much about the trial what would there be any <unk>.

A reason to believe that would that would be major differences from being fed hunches from trial that you know include a pre and post transplant patients, but there any reason why you would exclude 1 of them or or not.

John M. Leonard: And then I'll follow-up. I want to make sure I understand the question. Are you asking from an outcome point of view, or are you asking from a design point of view?

Then I have a follow up.

I I don't want to make sure I understand the question are you asking from an outcome point of view or are you asking about from a design point of view.

From a design point of view.

Yeah, I I'd say, it's still a little early to speak specifically about the design of what we're gonna be doing with 50, Oh on I think they're a general principles that people broadly apply that you should anticipate in in the early studies, but once we get regulatory clearance will go integral.

John M. Leonard: Yeah, I'd say it's still a little early to speak specifically about the design of what we're going to be doing with 501. I think there are general principles that people broadly apply that you should anticipate in early studies, but once we get regulatory clearance, we'll go into greater detail as to exactly what we're going to do. We certainly, you know, looking ahead, when, you know, as you referred to the University of Washington's Fred Hutchinson results, we look to that as a helpful guide to set some expectations in terms of what might work, and some of that logic supports our thinking about WT1, but there are differences between our particular approach and the one that they applied.

Later detail as to exactly what we're gonna do we certainly you know looking ahead, yeah. When you know as you referred to the University of Washington, Fred Hutchinson results. We we look to that as a helpful Guide to set some expectations in terms of.

What might work in some of that logic supports Ah are thinking about W. T..1.

But there's differences between our particular approach and the 1 that they applied.

Great. Thank you and maybe [noise].

John M. Leonard: Great, thank you. And maybe you can speak to the high-level strategy for the new company that you've created with JMOAP and Blackstone. Did you think these new CART cells will explore new targets, or do you plan to just produce better sales with, you know, existing well-established CART targets? You can just speak to that. Thank you. So the new company will have its own story to tell as it moves along.

If you can speak to the high level strategy for the New company 30 of Crazy with J mock on Blackstone did you think this new car T cells will they explore new targets or or do you plan to just produce better sales with you know X existing well established khaki targets it could just be.

To that thank you.

[noise] so the the newco will have its own a story to tell as it moves along it's an independent company, which we have a significant ownership position and we're very very excited about that and I'll remind you that we're supplying.

John M. Leonard: It's an independent company that we have a significant ownership position in. We're very, very excited about that. And I'll remind you that we're supplying the Allogenic platform, which we have not broadly disclosed. It is available to them, and you should look forward to hearing a little bit more about that as we go forward. Here, but it's our expectation that they'll pursue whatever they think the modality best addresses, and that could apply to existing Cartier targets, and with the switchable protein that actually targets these lymphocytes, they are certainly in a position where they could potentially explore other targets that I think that technology uniquely helps them to do. But, That will be their story to tell as they lay out their plans going forward.

The aloe genetic Ah platform that we have not broadly disclosed it is available to them and you should look forward to hearing a little bit more about that as we go forward here.

But it's our expectation that bill pursue whatever they think the modality best addresses and that could apply to existing khaki targets and with the switchable protein that actually targets just went the sites. They certainly in a position on where they could potentially explore.

Other targets that I think that technology uniquely helps them to do but.

That that will be their story to tell let's say lay out their plans going forward.

John M. Leonard: Great, thank you for taking my questions. The next question comes from Jack Allen from Baird. Please go ahead.

Great. Thank you for taking my question.

From the.

The next question comes from Jack Alan from Bear. Please go ahead.

Operator: Thank you so much for taking the questions and congratulations on all the progress this quarter. We wanted to ask about your most recent thoughts surrounding the potential for redosing with your L&P platform. How are you thinking about the potential need to redose NTLA 2001?

Hi, Thank you so much for taking the questions and congratulations on on the progress of quarter.

We wanted to ask about your most recent thoughts on and the potential for Redosing with your own P. Platform are you thinking about the potential need to Redose N. T. O. N 2001 is just something that's on the radar or are you very confident that 1 dose is gonna be enough to drive meaningful clinical benefit and then a quick follow up question was how frequently on your wrist.

John M. Leonard: Is this something that's on the radar, or are you very confident that one dose is going to be enough to drive meaningful clinical benefit? And then our quick follow-up question was, how frequently are you receiving data from the study of NTLA 2001? I know it's a single-arm study, and I'd imagine you are receiving data on some sort of rolling basis. Any color you can provide there would be great as well.

Leaving data from the study of N T O N 2001, I know, it's a single arm studying I imagine you're receiving data on some sort of rolling basis any color you provide there would be great as well. Thank you so much.

John M. Leonard: Thank you so much. I'll take that. We certainly look very, very carefully at the data as it comes in, and it's an ongoing interaction with the investigation sites, and our development team is in daily contact with them as that study progresses. It's not a blinded study, so we have the benefit of getting information and interacting with the investigators as we go. And then you're going to remind me of the first question that you asked me. I just, I'm sorry. Oh, redoing it.

I'll.

I'll take that.

We certainly looked very very carefully at the data as it comes in and it's not going interaction with the investigation sites in in the art about me team is in daily contact with them as such study progressive So it's not a blinded studies. So we have the benefits of getting information.

And interacting with the investigators as as we go.

And the you're gonna have to remind me the first the.

First question that you you asked me I just.

I'm, sorry, Oh, Redosing I'm sorry, so.

John M. Leonard: So, uh, yeah, the way we think about redosing is the LMP certainly enable that, and that's by their very nature and one of the reasons that we chose them way back at the very beginning. They're not inherently immunogenic, and they do not raise neutralizing antibodies, which means that if we need a redose, we can redose. The redosing approach, in the case of 20-01, for the patients participating in our first in human study has been to say to patients that once we determine an optimal biological dose, we will make that available to patients who did not receive it.

Yeah. The way, we think about Redosing is the L. M. P's, certainly enable that and that's by their very nature and and 1 of the reasons that we chose them way back it's at the very beginning they're not inherently immunogenic and they do not raise neutralizing antibodies, which means that if we need to read those we can.

Those are 3 dosing approach in the case of 20th on 1 for the patients participating in our first and human study has been to say to patients that once we determine an optimal biological dose we will make that available to patients who did not receive that that's not formally.

John M. Leonard: That's not formally a part of this particular protocol, but that is something that will be made available to the patients as part of the program, and going forward as we think about dosing patients in general, once we have the final format and final dose, again, it's our expectation, and this is based on the preclinical results that we have, that the likelihood of the required redos, assuming an optimal dose given in the first place, It was awesome. Thank you so much for the color.

Part of this particular protocol, but that is something that will be made available to the patient says the program per se. It's you know.

And going forward as we think about dosing patients and generally once we have the final format and finals dosing.

Again, it's it's our expectation and this is based on the preclinical result, so we have that the likelihood of require read those assuming an optimal dose is given in the first place.

Is is remote.

Mm probably not necessary.

Awesome. Thank you so much for calling.

Operator: The next question comes from Yanen Zoo from Wells Fargo. Please go ahead. Hi, thanks for taking my question. So I was wondering if there is anything that might be different from the T cells of AML patients compared with B-cell lymphoma patients that might affect your ability to grow out and manufacture CARTs in those, in those, from those patients. Thanks.

The next question comes from you on in Zoo from Wells Fargo. Please go ahead.

Hi, Thanks for taking my question. So I was wondering for.

On a M L patient for the 5000 Island program.

Is there anything.

It didn't it might be different from the T cells from an outpatient compared with Ah Ah Ah Ah.

Lymphoma patients that might affect your the ability to grow out and Ah manufacturing car teeth in those from those patient.

[noise], David do you want to [noise].

David Neil Lebowitz: David, do you want to try to address that? Is there any reason that we should be aware of underlying differences in cells based on what we're doing relative to other cell types?

Tried to address not deserved any reason that we should be aware of of underlying differences in sales based on what we're doing relative to other cell types.

David Neil Lebowitz: Yeah, thanks. We don't think that patients with AML have any tragic issues, let's say, with their T cells if they can't be manufactured well. Of course, we'll get more experience in the trial when we go forward, but so far, we have no evidence of that, and a quick follow-up on your transcript, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, uh, I think in the past you mentioned that you have a gentler approach to transfection and manufacturing either the TCR or the CART cells. Could you elaborate a little more on that and what might be the advantage to traditional CART manufacturing?

Another program.

No. Thanks, we we don't think that patients with their male had any riddick uhm.

Sure, let's say with their cheese sounds that they can't be manufactured well, Chris will get more experienced from the trial. When we go forward, but so far we have no evidence of that.

Got it and.

And a quick photo hop on your crash at.

Ah transfer a transaction Methodist I think in a path you mentioned that you have a chancellor approach to transfection and ER manufacture and manufacturing the the either the T C R or the car T cells could you elaborate I did on more on.

On that and what what might be the advantage to a traditional khaki manufacturing. Thanks.

John M. Leonard: Thank you. Yeah, thanks for the question. It's something that we're really proud of, that our scientific team has worked on and developed. But we don't share the specifics of how we do that.

Yeah. Thanks for the question, it's something that we're really proud of a better scientific team.

Is worked on and and and developed we don't share the specifics of how we do that we think that that is an area of competitive advantage for us for the simple reason that standard out of the box electroporation damage itself certainly in effect.

John M. Leonard: We think that that is an area of competitive advantage for us, for the simple reason that standard out-of-the-box electropuration damages cells. It's certainly an effective way of getting material into cells, and it's widely used. But the approach that we've taken does that at least as well, maintains cell viability, and allows cells to behave as if they had never been transduced in the first place from a division point of view. We think that's going to translate into dosing advantages for patients.

The way of getting material Incels and it's it's widely used but the approach that we've taken does that at least as well maintains cell viability Ah allows cells to behave as if they had never been transducer from the first place.

From a division point of view, we think that's going to translate into dosing advantages for patients and importantly, when you look at the genetic architecture of those sells once they've been transduced.

John M. Leonard: And importantly, when you look at the genetic architecture of those cells, once they've been transduced, it's maintained. I mean, there's no inherent damage done to the genetic architecture by our transduction technique, irrespective of the editing itself, which is certainly not the case for standard like repair. So, you know, our approach is that, you know, the editing is part of the story. How you do the editing is also critically important, and what you want to do, ultimately, is have cells that are as normal as possible. possible and advantage to the greatest extent so that they'll behave well once a patient's, Thanks for taking the question. The next question comes from Tony Butler from Roth Capital. Please go ahead.

It's it's maintained I mean, there's no inherent damage done to the genetic architecture fire transduction technique irrespective of the editing itself, which is certainly not the case first standard electroporation. So you know it's R approaches that you know the editing as part of the story how.

You do the editing is also critically important and what you Wanna do ultimately has have cells that are as normal as possible an advantage to the greatest extent, so that they'll behave well once a patient's dose.

Great. Thanks for taking the questions.

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

[noise] John.

John M. Leonard: John, 5, or maybe the first program in cell therapy, I wanted to address what may be a very simplistic question, and that is: Back when you and the team sat down to think about what would be your first target, you arrived at AML and WT1, which is great. The question is, Was there any specific reason for that particular program that is a blood tumor target versus, maybe say, a solid tumor target?

5 zero O 1 or maybe the first program and and still therapy I wanted to.

The address what may be a very simplistic question and that is.

Back when you're on the team sat down to think about what would be your first target.

You arrived at a M L and W. T..1 which is great. The question is.

Was there any specific reason for that particular program that has a blood tumor target versus maybe say a solid tumor target and I'm asking not because it's W. T 1 or because it's a M L. But I would I just based upon the way that I perceive you've laid out all the other pro.

John M. Leonard: And I'm asking not because it's WT1 or because it's AML, but I would, just based upon the way that I perceive you've laid out all the other programs, there may be some learnings you want to take from a particular set of experiments. And this may give you, or this target and this blood tumor may give you the answer to those particular questions. And I'm curious if that's correct and if you would share that.

Grams, there may be some learning she wanna take from a particular.

Set of experiments and dismayed give you or this target in this Ah Ah Ah blood tumor may give you the answer to those particular questions and I'm curious if that's correct and if you make sure that thank you.

John M. Leonard: I think it's an astute observation of how we think about our work. We try very hard to isolate a key variable, get the clearest answer that we can with respect to that variable, and then move on from there. So in the case of engineered cells, we believe, as we have presented extensively in other venues, that a T-cell receptor-based approach brings tremendous opportunities and moves outside the fairly limited space that Cartesol's cells are active in.

I think it's an astute observation of how we think about our work we try very hard to isolate the key variable.

Get the clearest answer that we can with respect to that variable and then move on from there. So in the case of engineered cells. We.

We believe as as we presented extensively in other venues that a T cell receptor based approach brings with a tremendous opportunities and moves outside the fairly limited space that car T cells are active.

Well, we want to determine was could we with our approach isolate healthy donor T. C ours developing editing paradigm that introduced those tcr's themselves and that we could show that they could work well we tried to do a strip away all of the other potential consult.

John M. Leonard: What we wanted to determine was whether we could, with our approach, isolate healthy donor TCRs, develop an editing paradigm that introduces those TCRs into cells, and whether we could show that they could work. What we tried to do was strip away all of the other potential confounding factors. Solid tumors have some, while liquid tumors tend to be less complex. They have their own complexity, for sure, but there are other factors that characterize solid tumors that don't apply to liquid tumors.

Being factors solid tumors have some liquid tumors tend to be less complex and they had their own complexity for sure but there's other factors that character I saw on Tuesday don't apply in liquid tumors.

John M. Leonard: And we thought, with AML and the high levels of WT1 expression that characterized it, it would be a wonderful test case for the overall thinking. And we're excited to see if, you know, our preclinical work is on target. And, you know, as David shared, we're at the point where we're going to find those things out because we're moving to the clinic by the end of this month. I'm grateful for your comments. There are no more questions in the queue.

And we thought with AML on the high levels that that'd be a T..1 expression that characterized us it'll be a wonderful test case for the overall thinking and we're excited to see if if you know are preclinical work is on target and you know as as David chaired we're at the point where where.

We're gonna find those things out because we're moving to the clinic by the end of this year.

I'm grateful for your comments.

There are no more questions in the queue. This concludes our question and answer session I'd like to turn the <unk> The conference back over to Ian Carp for any closing remarks.

John M. Leonard: This concludes our question and answer session. I'd like to turn the conference back to Ian Karp for any closing remarks. Great, thank you so much, and thank you everyone for joining us today and for your continued interest in supporting us and Talia. We look forward to updating you on our progress, and we hope everyone has a great day. Bye now. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.

Great. Thank you so much and thank you everyone for joining us today and for your continued interest and it's important and tell Ya.

Look forward to updating you on our progress and we hope everyone has a great day bye now.

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

[music].