Q2 2022 Intellia Therapeutics Inc Earnings Call

Good morning and welcome to the Intellia Therapeutics' second quarter 2022 financial results conference call.

Good morning, and welcome to the <unk> Therapeutics second quarter 2022 financial results Conference call. My name is Andrew and I'll be your conference operator today.

My name is Andrew and I will be your conference operator today.

Owing formal remarks, we will open the call up for a question and answer session.

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

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

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

Following formal remarks, we will open the call up for a question and answer session.

I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and corporate communications at <unk>. Please proceed.

<unk>.

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.

Thank you operator, and good morning, everyone welcome to <unk> Therapeutics second quarter 2022 earnings call.

Earlier. This morning until you issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call.

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

<unk> is being broadcast live and a replay will be archived on the Companys website.

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

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

Joining me from Italia are Dr. John Leonard Chief Executive Officer, Dr. David Lebel, Chief Medical Officer, Dr. Laura Sepp Blandino, Chief Scientific Officer, and Glenn Goddard Chief Financial Officer.

John will begin with an overview of recent business highlights.

David will provide an update on our clinical programs with a focus on until late 'twenty, one and 'twenty two.

Laura will then provide an update to our ex vivo strategy.

Ken will then review and tell his financial results from the second quarter and John will provide some final remarks before we open the call up for Q&A.

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

And with that I'll now turn the call over to John .

If anyone requires operator assistance during the conference, please press star then zero on your telephone keypad.

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

I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia.

At <unk>, we're building the industry's leading genome editing company, we're deploying the broadest and deepest toolbox, including novel editing and delivery solutions harness the immense power of CRISPR based technologies for in vivo and ex vivo therapeutic applications, each with the potential to revolutionize medicine.

Please proceed.

Thank you, operator, and good morning, everyone.

During the second quarter and more recently, we've continued to advance our full spectrum pipeline and platform.

Welcome to Intellia Therapeutics' second quarter 2022 earnings call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call.

Starting with him until late 'twenty, one we've made excellent progress in the ongoing phase one study in June we presented additional clinical evidence that until late 'twenty, one led to deep and durable GTR reductions following a onetime administration across all therapeutically relevant doses JV.

This release can be found on the investors and media section of Intellia's website at IntelliaTX.com.

David will provide a recap of the data presented in diesel and elaborate on the latest findings from the study.

In addition, dosing is now completed and the dose escalation portion of the cardiomyopathy arm with the more expansive data set we're finalizing selection of our fixed dose corresponding to the 0.7 make per king dose to evaluate in the dose expansion portion of the cardiomyopathy arm.

Our second and people knockout candidate until late 'twenty, two has strong momentum and we remain on track to share first look at safety and activity data from the first in human study later this year.

This will represent an opportunity to not only demonstrate the potential of <unk> as a treatment for people living with hereditary angioedema, but also the reproducibility of our modulus platform.

With our ex vivo efforts, we're advancing unique and proprietary allogeneic technology, which leverages, our LNP based cell engineering platform.

Our novel approach is designed to overcome rejection by host T and NK cells, a key limitation to the durability of current allogeneic investigational therapies based on our compelling preclinical data, we are making a strategic shift to focus on exclusively developing allogeneic cell therapies for a lead X.

Legal program until at 50, or one which you may recall. This is an autologous program. We're pivoting to an allogeneic version, which is now in preclinical development, Laura will share more on our decision and the advantages of our allogeneic platform for patient shortly.

Finally, <unk> remains in a strong financial position, we ended the quarter with $907 million in cash, which gives us the capacity to continue to prosecute the strategic priorities, we set forth at the beginning of this year.

I'll now turn it over to David.

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

Thanks, John and welcome everyone.

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

Beginning with 'twenty, one for the treatment of <unk>.

Joseph <unk> Amyloidosis, we were thrilled to report continued positive interim data from the Polyneuropathy arm of our ongoing phase one study at <unk> International liver Congress in June .

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

Joining me from Intellia are Dr. John Leonard, Chief Executive Officer, Dr. David Leblois, Chief Medical Officer, Dr. Laura Sepp Lorenzino, Chief Scientific Officer, and Glenn Goddard, Chief Financial Officer.

John will begin with an overview of recent business highlights.

These data provided early confirmation that deep reductions in the disease, causing protein.

By a onetime genome editing treatments are in fact durable overtime.

Are all four dose levels tested in the dose escalation portion I think in the <unk> with 21 resulted in sustained reductions in protein levels opened the follow up period, ranging from six months to a year.

That's a <unk> seven and one milligram per kilogram doses 21 led to a greater than 85% New Ctr reduction at day 28, with a maximum reduction of 97% 98% respectively.

These results remained durable through the six months with ongoing follow up.

We continue to believe deep durable and remarkably consistent levels of protein reduction support 'twenty one's potential as a one time treatment that can halt and possibly reverse the disease.

In addition, we continue to make great progress in the cardiomyopathy setting.

Recall the primary objectives in both arms are to establish safety and optimal dose to move forward and potential pivotal studies.

There are now over 30 individuals who have been dosed with 'twenty one across both the Polyneuropathy and cardiomyopathy arms with the first ever systemically administered in vivo CRISPR candidate.

But the cardiomyopathy arm, we announced today the completion of the dose escalation portion.

Why are we look forward to presenting the first interim readout from the cardiomyopathy arm. Later this year. We are pleased to share that the initial findings have been consistent with the data previously ported from the Polyneuropathy arm at easily.

Based on the recent data at <unk>, 7% in one milligram per kilogram have very similar GTR reduction have been generally well tolerated. We are now finalizing a six.

Our selection.

At or near a fixed dose equivalent of 0.7 milligrams per kilogram for evaluation in the dose expansion portion.

We also announced today that we plan to evaluate the same fixed dose and a second cohort in the dose expansion portion of the Polyneuropathy arm.

The decision to study a second dose was based on three main factors.

First the emerging data from the dose escalation portion of the cardiomyopathy arm.

Still on a small number of patients dosed initial GTR reduction data.

Indistinguishable after two doses tested.

Second the comparability of our performance at <unk> seven milligrams per kilogram and one point out per milligram per kilogram doses in the dose escalation portion of the Polyneuropathy arm.

And third while 21 has been generally well tolerated there was a recent adverse event in a patient dosed in the 80 milligram dose expansion cohort in the Polyneuropathy arm that informed our.

Our decision.

A significant elevation in liver enzymes and visitation at May 28 was observed in a routine laboratory assessment.

Liberate outside to return to normal levels without medical intervention.

Patient was symptomatic and had no increase in bilirubin.

That was considered non serviced by the investigator and deemed possibly related to study drug.

As a result, we plan to evaluate new common six dose in both arms to better inform our future pivotal study design in line with the goal of the phase one study to identify a dose that delivers the maximum amount of benefit to patients at the lowest dose possible.

Overall this strategy reflects our strong conviction that 'twenty, one and achieved a deep levels of TTL reduction expected to potentially halt and reverse the disease.

We plan to submit a protocol amendment in the coming days.

In addition, we expect to present initial safety data from the 80 milligram dose expansion cohort from the Polyneuropathy arm.

The upcoming 21 data readout later this year.

David will provide an update on our clinical programs with a focus on MTLA 2001 and 2002.

We are incredibly proud of all the rapid progress in our ongoing phase one study at 20 O one and subject to regulatory feedback from the protocol Amendment, we continue to expect to complete enrollment by the end of 2022.

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

As a reminder, we are targeting the KL KC one gene in the liver.

You reduced plasma <unk> crime and its activity.

Other modalities have shown that a 60% reduction in carrier activity leads to a therapeutically relevant reduction in <unk> attacks.

With 20 year or two we've shown compelling data in nonhuman primates, where we have achieved and sustained greater than 90% reduction of both <unk> protein and its activity after a single dose.

These results translate to humans 22, it could be a transformative new treatment option for people living with H I G.

Yeah.

We continue to make steady progress in the dose escalation portion of our phase <unk> study and look forward to sharing initial results from both the 25 and.

75 milligram dose cohort later this year.

This interim data readout is expected to include safety calix crime reduction and <unk> attach rate data.

These results will offer an initial view of the safety and activity profile of 20th June and potentially demonstrate proof of concept for the modularity of our composite Terry.

LNG platform.

Laura will then provide an update to our ex vivo strategy.

I'll now turn over the call to allow us to provide updates on our ex vivo pipeline and R&D progress.

Glenn will then review Intellia's financial results from the second quarter, and John will provide some final remarks before we open the call up for Q&A.

Thanks, David.

And with that, I'll now turn the call over to John.

Starting with probably like an hour with medication to focus exclusively on developing allogeneic investigational ex vivo therapy and the impact this will have when I work, Kevin Ultra allows us immediately.

Thank you, Ian, and thank you all for joining us this morning.

One clinical program.

As many of you.

There were some of the key challenges without all of the cell therapies for cancer treatments.

First patients with cancer, who have already been exposed to cytotoxic treatments do not provide an ideal starting point for connecting L. T cell <unk>.

Subsequent engineering.

In addition, the complex manufacturing process required associated high cost for this therapy.

Clearly there are those to treatment.

In response, mainly in the field have focused on developing off the shelf solutions. However, maybe somebody makes us an optimum allogeneic submission needs to meet the following criteria.

First sales should be sourced from healthy donors and Ian Bailey give Anna both for our new strategy.

There needs to be inefficient in many countries and process able to produce a hotel that we desired attributes at the company dollar cost.

I'm sorry.

Great Big and important.

Yes.

Percents for long periods of time, allowing for continued antitumor activity.

These last two area persistence remains unfold and recent clinical data has clearly demonstrated that lasting responses.

But with kind of an approach.

At Intellia, we're building the industry's leading genome editing company. We're deploying the broadest and deepest toolbox, including novel editing and delivery solutions, to harness the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications, each with the potential to revolutionize medicine.

I think we have developed a proprietary allogeneic black Swan, which literature novel combination of sequential.

During the second quarter, and more recently, we've continued to advance our full spectrum pipeline and platform.

Our preclinical data strongly supports our highly differentiated evergreen strategy should achieve both high antitumor activity and the persistence required for sustained responses in patients.

Starting with MTLA 2001, we've made excellent progress in the ongoing phase one study. In June, we presented additional clinical evidence that MTLA 2001 led to deep and durable TTR reductions following a one-time administration across all therapeutically relevant doses.

David will provide a recap of the data presented at ESL and elaborate on the latest findings from the study. In addition, dosing is now completed in the dose escalation portion of the cardiomyopathy arm.

Our allogeneic, that's one piece of technology that is already underpinned the research collaborations with Abbvie.

And our wholly owned and 61 can be like.

With the more expansive data set, we're finalizing selection of a fixed dose corresponding to the 0.7 mg per kg dose to evaluate in the dose expansion portion of the cardiomyopathy arm.

Now for Indian AC tier one we have concluded it is in the best interest of patients to pivot as quickly as possible to an allogeneic program using the same PCI.

Our second in vivo knockout candidate, NTLA-2002, has strong momentum, and we remain on track, to share a first look at safety and activity data from the first in-human study later this year.

This will represent an opportunity to not only demonstrate the potential of NTLA-2002, as a treatment for people living with hereditary angioedema, but also the reproducibility of our modular platform.

The decision to discontinue the current phase one study is not due to any safety or efficacy data emerging from the trial.

With our ex vivo efforts, we're advancing unique and proprietary allogeneic technology, which leverages our LNP-based cell engineering platform. Our novel approach is designed to overcome rejection by host T and NK cells, a key limitation, to the durability of current allogeneic investigational therapies.

It is based on the potential to consistently deliver high quality product by switching to an allogeneic question.

Based on our compelling preclinical data, we are making a strategic shift to focus on, exclusively developing allogeneic cell therapies.

Most importantly, we believe an allogeneic version of Indian AC <unk>, who will provide significant advantages to patients fighting an extremely aggressive type of cancer.

For a lead ex vivo program, NTLA-5001, which you may recall is an autologous program, we, are pivoting to an allogeneic version, which is now in preclinical development.

In further support of suspicion with tens of percent additional preclinical data on our allogeneic platform at the synthetic control late in 2022.

Our platform innovations continue to support our robust research engine and the hope of wholly owned and partner investigation increased Burbank stacks.

I'll now hand over the call to Glenn <unk>.

CFO , who will provide an overview of our second quarter financial results.

Laura will share more on our decision and the advantages of our allogeneic platform, for patients shortly.

Thank you Laura good morning, everyone.

I can tell you continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform, it's a challenging market environment.

Finally, NTLA remains in a strong financial position. We ended the quarter with $907 million in cash, which gives us the capacity to continue, to prosecute the strategic priorities we set forth at the beginning of this year.

Cash cash equivalents in marketable securities were approximately $907 million as of June 32022, compared to $1 1 billion.

December 31 2021.

The decrease was driven by cash used to fund operations of approximately $191 2 million.

As well as the acquisition of worry right $445 million.

The decrease was offset in part by $38 9 million in net equity proceeds raised from the company's aftermarket agreement and $14 3 million and proceeds from employee based stock plans.

Our collaboration revenue increased by seven 5 million to $14 million during the second quarter of 2022 compared to $6 6 million during the second quarter of 2021.

The increase was mainly driven by our collaborations with avid <unk> and type of Arnaud.

R&D expenses increased by 31 3 million to $90 2 million during the second quarter of 2022 compared to $58 9 million during the second quarter of 2021.

This increase was driven by the advancement of our lead programs and research and development personnel growth to support these programs.

Our G&A expenses increased by $5 4 million to $22 1 million during the second quarter of 2022 compared to $16 7 million during the second quarter of 2021.

This increase was mainly related to employee related expenses, including stock based compensation of $4 $5 million.

I'll now turn it over to David.

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

Thanks, John, and welcome, everyone.

Beginning with 2001 for the treatment of transtyrene amyloidosis, or ATTR amyloidosis, we were, thrilled to report continued positive interim data from the polyneuropathy arm of our ongoing phase one study at ESL's International Liver Congress in June.

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

Thank you Glenn it's been an incredibly active quarter and we continue to make significant progress in our mission to bring forth a pipeline of CRISPR based medicines to patients in need.

These data provided early confirmation that deep reductions in a disease-causing protein, achieved by a one-time genome editing treatment are, in fact, durable over time. At all four dose levels tested in the dose escalation portion, editing the PTR gene with, 2001 resulted in sustained reductions in protein levels over the follow-up period ranging from six months to a year. At the 0.7 and 1.0 milligram per kilogram doses, 2001 led to a greater than 85% mean, PTR reduction at day 28, with maximum reductions of 97% and 98%, respectively. These results remained durable through the six months of ongoing follow-up.

We continue to believe these deep, durable, and remarkably consistent levels of protein, reduction support 2001's potential as a one-time treatment that could halt and possibly reverse the disease.

In addition, we continue to make great progress in the cardiomyopathy arm of the study.

Having previously led the development for some of our industry's most groundbreaking medicines I know from experience how important it is to follow the science and adapt quickly to information as it becomes available.

I'm confident that the decisions our team has made across the pipeline are in the best interest of patients and our shareholders.

All the primary objectives in both arms are to establish safety and an optimal dose to, move forward in potential pivotal studies.

Looking ahead to the remainder of the year, we will continue to advance the clinical development of NPL late 'twenty one.

There are now over 30 individuals who have been dosed with 2001 across both the polyneuropathy, and cardiomyopathy arms with the first ever systemically administered in vivo CRISPR candidate. For the cardiomyopathy arm, we announced today the completion of the dose escalation portion.

Like 'twenty, two as well as execute against our strategic priorities of particular note. We plan to share interim data updates from until late 'twenty, one and a first look at the safety and performance of until late 'twenty two.

While we look forward to presenting the first interim readout from the cardiomyopathy arm later this year, we are pleased to share that the initial findings have been consistent with the data previously reported from the polyneuropathy arm at EASL. Based on the recent data, the 0.7 and 1.0 milligrams per kilogram have very similar TTR reductions, have been generally well tolerated.

We are now finalizing a fixed-dose selection at or near a fixed-dose equivalent of 0.7 milligrams per kilogram, for evaluation in the dose expansion portion.

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

Operator.

We also announced today that we plan to evaluate the same fixed-dose in a second cohort in the dose expansion portion of the polyneuropathy arm. The decision to study a second dose was based on three main factors.

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

If youre using a speakerphone please pick up your handset before pressing the keys if at any time. Your question has been addressed and you'd like to withdraw. Your question. Please press Star then two.

Please limit yourself to one question and one follow up.

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

First, the emerging data from the dose escalation portion of the cardiomyopathy arm.

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

While still in a small number of patients dosed, initial TTR reduction data is indistinguishable at the two doses tested. Second, the comparability of performance at the 0.7 milligrams per kilogram and 1.0 per milligram per kilogram doses, in the dose escalation portion of the polyneuropathy arm.

Alright, thanks for the update and for taking our questions.

What are your top one or two questions for Apollo B heading into ISR data presentation on August eight.

Assuming you plan to attend at least virtually thank you.

Thanks June 1st of all we're really excited about the outcome because we think it validates what we believe for a long time, which is the best way to deal with.

Any form of <unk> amyloidosis in particular, <unk> amyloidosis is to reduce the offending protein to low levels.

We of course had been targeting very very deep reductions in we think that we'll be able to.

Take what we've already demonstrated and apply it to patients with cardiomyopathy and would expect to see.

Profound clinical benefit as a result, but.

I think like all observers were interested in getting the full data set in terms of how the patient is performed.

Obviously six minute walk test is a particular readout, but some of the harder endpoints I think are really important to understand which will inform how we think about.

Studying these patients I don't know David if there's anything of particular interest to you that you might want to expand on.

I think a couple of other things we'll be interested in how patients did who received a parameter or didn't receive fabulous it seemed to be part of the story.

On the biggest piece, we do think we can do better than what they did because of the deeper reductions we got in GTR. So as we designed our trial at that point will be important to show how.

How many might show better efficacy than we've seen in that trial.

Thank you.

Thank you.

And third, while 21 has been generally well tolerated, there was a recent adverse event in a patient dosed in the 80-milligram dose expansion cohort, in the polyneuropathy arm that informed our decision. A significant elevation in liver enzymes in this patient at day 28 was observed in a routine laboratory assessment. The liver enzymes returned to normal levels without medical intervention. The patient was asymptomatic and had no increase in bilirubin. The event was considered non-serious by the investigator and deemed possibly related to study drug.

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

As a result, we plan to evaluate a common fixed dose in both arms to better inform our future pivotal study design, in line with the goal of the Phase I study to identify a dose that delivers the maximum amount of benefit to patients at the lowest dose possible.

Overall, this strategy reflects our strong conviction that 21 can achieve the deep levels of TTR reduction, expected to potentially halt and reverse the disease.

We plan to submit a protocol amendment in the coming days.

In addition, we expect to present initial safety data from the 80-milligram dose expansion cohort, from the polyneuropathy arm at the upcoming 2001 data readout later this year.

This filing on for Marty.

Just a follow up on Apple or <unk> like have you how does the data inform your next steps in the designs, whether it be able to like what you would rely on the six minute walk test.

Okay and.

And find auto bake and prefer like harder endpoint.

Well as <unk>.

First pass I think the six minute walk test as some utility, but it's really not the most definitive endpoint in terms of how regulators.

Our regulators.

Physicians and even payers ultimately think about the effects of these drugs so for us.

That's at the core of our program, but there's no doubt at six minute walk as a useful read out to some degree of improvement.

We think that what we've seen so far again as validation of the entire knockdown hypothesis for cardiomyopathy.

David any other thoughts you can say we've been talking for a while that reduced think the most important endpoints are of cardiovascular events and mortality.

No it was.

You don't see that yet in this trial interest smaller trials and some of the others. It's also fairly short term.

Will be important to show that benefit by lowering GTR.

Thanks.

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

Good morning, guys. Thanks for taking our questions and congrats on all the progress I wanted to pivot a little bit to a different set of questions because I'm sure you'll get a number of other Apollo b questions.

We are incredibly proud of all the rapid progress in our ongoing Phase I study of 2001.

And subject to regulatory feedback from the protocol amendment, we continue to expect to complete enrollment by the end of 2022.

The H H E a data expected in the second half.

Outlined in the press release safety, I guess telecom reduction in attack rates, but.

Turning now to 2002, our investigational therapy for the treatment of hereditary angioedema, or HAE. As a reminder, we are targeting the KLKB1 gene in the liver to permanently reduce plasma calocrine and its activity. Other modalities have shown that a 60% reduction in calocrine activity leads to a therapeutically relevant reduction in HAE attacks. With 2002, we've shown compelling data in non-human primates where we have achieved and sustained greater than 90% reductions, of both calocrine protein and its activity after a single dose. If these results translate to humans, 2002 could be a transformative new treatment option for people living with HAE.

Heading into it what should we think about in terms of relevant comps is it line of Italian mab as a barrel trial start or something else and as a follow up for the 2003 I didn't see any specific guidance as to when the IMD or the equivalent filing would be as opposed to the 3001 guidance. So since 2000.

We continue to make steady progress in the dose escalation portion of our Phase I-II study, and look forward to sharing initial results from both the 25- and 75-milligram dose cohorts later this year. This interim data readout is expected to include safety, calocrine reduction, and HAE attack rate data.

These results will offer an initial view of the safety and activity profile of 2002, and potentially demonstrate proof of concept for the modularity of our proprietary CRISPR-based LNT platform.

I'll now turn over the call to Laura to provide updates on our ex vivo pipeline and R&D progress.

Program is generally I guess shared has shared attributes between 2001 2002 and now 2003 is there anything unique about the <unk> gene or so Mr. Pinot one gene that warrants a broader window for IND or equivalent filing.

Thanks, David.

So we can do the 2003 question first.

I'll start with highlighting our recent decision to focus exclusively on developing allogeneic investigational ex vivo therapies, and the impact this will have on our current autologous MDLA-5001 clinical program.

When we get to the appropriate point, we will issue guidance as that program moves along which is typically how we do it.

As many of you are aware, some of the key challenges with autologous cell therapies for cancer treatments are well known. First, patients with cancer who have already been exposed to psychotoxic treatments, do not provide an ideal starting point for collecting healthy cells for subsequent engineering. In addition, the complex manufacturing process required and associated high cost for these therapies present further hurdles to treatment.

In response, many in the field have focused on developing off-the-shelf solutions.

However, the development of an optimal allogeneic solution needs to meet the following criteria. First, cells should be sourced from healthy donors and be readily available for administration. Second, there needs to be an efficient manufacturing process able to produce a full product with desired attributes at an accompanying lower cost.

And finally, of critical importance, these engineered cells must process for long periods of time, allowing for continued anti-tumor activity.

At Indalia, we have developed a proprietary allogeneic platform, which leverages a novel combination of sequential gene edits. Our preclinical data strongly supports that our highly differentiated editing strategy should achieve both high anti-tumor activity, and the persistence required for sustained responses in patients.

This last key area, persistence, remains an untold hurdle.

And recent clinical data has clearly demonstrated that lasting responses are not achieved with current approaches.

Our Allogeneic platform is a technology that already underpins the recent collaborations with Avansal and Graverna and our wholly owned MDLA-601 candidate. Now for MDLA-601, we have concluded it is in the best interest of patients to pivot as quickly as possible to an allogeneic version of this program using the same TCR.

Programs are related to each other but they are distinct and so I think it's important to keep that in mind remember that 3001 inch and insertion at a different gene at a different locus.

<unk> 2003 targets the offending gene itself <unk> so.

<unk> 3001 is a little bit ahead of 2003. They are independent programs, we designed them in a way that if we choose to we can bring them together in the same patient.

But at this point they are separate from each other.

With respect to H E.

We look at the standard of care as point of departure, and we think that Tech zero has set the relevant benchmark here.

We note that there are other agents that have met similar sorts of outcomes and all of that is tied to the same sort of.

Biological reasoning, which is inhibiting or reducing <unk> levels and that's exactly the approach that we're taking what we've seen is that the.

The bigger the effect the more of a pick up you get from a clinical endpoint point of view, so with our approach, which extrapolate from the data that we've seen with PPR already we believe that we should be well on our way too.

Minimally meeting the levels they are.

Reported out and perhaps surpassing them, which is of course our objective.

Great. Thanks, so much.

Sure.

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

Thank you for taking my questions. So I have one question regarding the one piece of liver enzyme elevation that at day 28 can you give a little bit more color regarding how many photos the upper limit norm that reach and how long did it last and thank you also dose 75 milligram for itchy patients.

A similar safety profile, there and then second question regarding.

Regarding itchy update you defeat Itchy attack May data just wondering if you can give a little bit more color would that be from each individual patient.

What was the comparison to the baseline and up say one or two months follow up if you can give a little bit more color regarding the attack rate.

I think that might be for questions.

I tried to.

Keep up with you.

With HLA E.

We'll show the data that we have which is starts with patients are at baseline and we'll give the follow up that we have and the expectation is we will give you as much information as we have at the time so the.

Actual format of the presentation.

Work on this we get to the point of actually doing it but and so I think you know it's been our principal to try to be as transparent.

Parents as possible and.

And.

I would expect that the general approach would be very very similar to what you've seen with PTR because the programs are.

So related.

With respect to the one patient in.

21 program.

We will go through the information that we have when we do a data disclosure later this year, but I'd just emphasize that.

As we shared in our script the data or the patient.

Extremely well, it's entirely asymptomatic laboratory abnormality that was transient in nature, but because we believe we have so much room on the efficacy side that.

Backing off the dose is a reasonable thing to do particularly since.

Our database has grown we've seen that.

It's essentially indistinguishable DPR reduction levels between the $7 1.1 milligram remember that when we did some of our first dose selections that was based on the century three people and as we've said all along is we do our phase one dose finding work information will accumulate that will influence our thinking and.

We've been very gratified with the outstanding safety profile.

The continuing excellent PTR performance of that David is there anything else you want.

I think a few other questions are in there for the HIV patients there have been no liver enzyme elevations in the safety has been.

Outstanding there in terms of the attack rate is to give you a little more detail. There we will be looking at individual patients in that analysis and the main way. This is done is by doing a are running now.

How many events are there before they get treated and then looking at how many events. There are after that and then it's usually over a period of two to four months, depending on the follow up.

I guess I'm just wondering the thought on the patient you asked about gene edits that remember at day 28, yes, one of the things that.

It's important to think about with <unk>.

As as a class.

We certainly look a lot like the class.

LNP outpatient or LST elevations when they occur tend to be right around the time of dosing, which is say one two or three and we've seen very low LTV.

Elevations, which we've reported on.

This is a transit funding held weeks later, which we have no idea if it's even related to the drug although we've considered that it may be possibly so and again was transient nature. So.

Again, just thinking about the bigger picture here and choosing the right dose that balances what we're trying to achieve with <unk>.

We've got lots of room to go on the efficacy side.

Thank you very much.

Sure.

The next question comes from Joseph <unk> with Cowen and company. Please go ahead.

Eric Good morning, and thank you for taking my question.

Just in terms of the flip for Pfizer zero, one over to allo, maybe when will that be in a place to move into the clinic.

Is that going to be our nearest term milestone and maybe how does that relate to what 60 or zero one could enter clinical development. Thank you.

Thanks for the question we haven't guided.

To a particular date yet.

Remember, what we've said which is the next incarnation of this will be with the same T cell receptor. So we remain.

Absolutely excited about.

Looking at T cell receptor biology.

One target et cetera, and remember that behind all of this is the logic that well car Ts are.

Certainly have their place and performed well and we have our own car T programs, we believe the larger opportunity with <unk>.

Cell based therapy for cancer.

As with other formats and TCR, we think is the most promising one of those so with respect to moving forward. We've got many of the <unk> in place if you will and it's really adapting our allogeneic platform, which we're incredibly excited about to that so as we finalize those steps will.

Sure that with the upcoming updates and.

Look forward to telling you more about that at that time.

Great and maybe just a quick follow up on fiber one are you going to present any of the data from the auto program. If you dosed any patients there.

We'll look at what.

What we get I mean, we're certainly following patients we've dosed remember that.

The decision to discontinue the current Phase I study is not due to any safety or efficacy data emerging from the trial. Instead, it is based on the potential to consistently deliver a high-quality cell product by switching to an allogeneic version.

Most importantly, we believe an allogeneic version of MDLA-601 will provide significant advantages to patients fighting an extremely aggressive type of cancer.

We are not making the switch based on any efficacy or safety readout. This is really just based on the merits of what we think is an allo approach as Laura laid out just you'll get better sells faster.

In further support of this decision, we plan to present additional preclinical data on our allogeneic platform at the Synthetic Conference later in 2022.

Our platform innovations continue to support our robust research engine and a host of wholly owned and partner investigational CRISPR-based therapies.

And now I hand over the call to Glenn, our CFO, who will provide an overview of our second quarter financial results.

That we think are going to just be superior performance to anything that an autologous format would be able to provide but as we collect information and think about future updates, particularly in the context of the Allo program, we'll think about that in insured as we see appropriate.

Thank you, Laura.

Thank you very much.

Good morning, everyone.

Sure.

Intelia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform amidst a challenging market environment. Our cash, cash equivalents, and marketable securities were approximately $907 million as of June 30, 2022, compared to $1.1 billion as of December 31, 2021. The decrease was driven by cash used to fund operations of approximately $191.2 million, as well as the acquisition of rewrite for $45 million. The decrease was offset in part by $38.9 million in net equity proceeds raised from the company's aftermarket agreement and $14.3 million in proceeds from employee-based stock plans.

Our collaboration revenue increased by $7.5 million to $14 million during the second quarter of 2022, compared to $6.6 million during the second quarter of 2021. The increase was mainly driven by our collaborations with Avancel and Kiberna.

The next question comes from Neil Another car with Piper Sandler. Please go ahead.

Our R&D expenses increased by $31.3 million to $90.2 million during the second quarter of 2022, compared to $58.9 million during the second quarter of 2021. This increase was driven by the advancement of our lead programs and research and development personnel growth to support these programs.

Our G&A expenses increased by $5.4 million to $22.1 million during the second quarter of 2022, compared to $16.7 million during the second quarter of 2021. This increase was mainly related to employee-related expenses, including stock-based compensation of $4.5 million.

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

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

Thank you, Glenn.

Hi, Thank you for taking my questions. So I guess a couple of them one on HIV programs. So given that there were some regulatory concerns during tagged zairo approval.

Exploration of the California pathway like what has been the regulatory feedback on this program and are there any additional safety monitoring requirements.

It's been an incredibly active quarter at Intellia. We continue to make significant progress in our mission to bring forth a pipeline of CRISPR-based, medicines to patients in need.

<unk> two program and then I will follow up.

Having previously led the development for some of our industry's most groundbreaking, medicines, I know from experience how important it is to follow the science and adapt quickly to information as it becomes available.

<unk> is moving very briskly.

All of our regulatory interactions have been pretty straightforward, but David I don't know if theres any additional color you want to sure.

I'm confident that the decisions our team has made across the pipeline are in the best, interest of patients and their shareholders.

Looking ahead to the remainder of the year, we will continue to advance the clinical development, of NTLA-2001 and NTLA-2002, as well as execute against our strategic priorities. A particular note, we plan to share in-room data updates from NTLA-2001 and a first look, at the safety and performance of NTLA-2002.

Say in multiple nationalities, we've had good feedback on what we're doing.

They are happy with the safety program that we put in place and as we've.

I alluded to Youll see Youll see the data later this year, but are also pleased with the safety we're seeing.

Got it and then for the fixed dosing regimen of <unk> seven can get clearer islands like it looks like safety and liver enzyme elevation was one of the key reasons to pursue that so the question that I have is like of the portal part D patients that that those to be Italy is there any other patients who had any anda.

And then innovations.

And if not significantly but it might not all incremental.

Innovations.

Well you've seen some of the data that we presented certainly around the time of infusion, you'll get very low level increases peacefully presented that information at the last.

Easel presentation I think there was an example of one patient who had just an excursion just outside the limits of normal at day 28.

So.

Yes, and that sensors other examples.

Alright, thank you.

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

Good morning, Thanks for taking my questions with regard to that decision secondly, second PTR study.

How much do you anticipate this will be linked development timelines and separately on the switch to allogeneic from your email program.

Could you just expand on the rationale behind pursuing a better product and.

Understanding that the construct here I'm, just trying to get a sense of the foundational work.

Right.

Maybe David can say a word about.

Any impact if any to the timeline and then I will have Laura take you through the thinking on the allo and why we're so excited about it but David I'll go first so yeah. Let me take you back to really ease or wherever you showed 15 patients from the Polyneuropathy program.

What we saw there was deep reduction start really starting at <unk>, three is where we'd see it durable and up through one milligram at that point.

It looks like the one milligram was slightly better than the <unk> seven and went forward with that country.

As we've said now we have more than 30 patients we have really multiples of the number of patients at <unk> seven so that with this increased data it's quite clear that.

Any efficacy at 27 and want a really indistinguishable.

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

So with that the.

We are now.

And you see the rate of enrollment at this point. The investigators are really excited about the program, we're doing very well so we.

We have a lot of information on patient cardiomyopathy, and what we.

We do going forward will still be able to enroll all the patients by the end of the year as we guided from everything we see and that has to do with the how.

How much we've learned and recall it with a cardiomyopathy patients. We did study both <unk> seven and one in order to pin down this question.

Drug development, you really want to go with the lowest dose that gives you that efficacy.

We are seeing in this program is a very flat dose response curve.

Laura you want to talk about the allo platform, a little bit and how we think about it.

We're pivoting.

Yes, no happy to do that so.

But what we've learned from our heavy but importantly for others.

Is that I think pointing to allogeneic platform not only to have a consistent solid product with high quality.

You know station manufacturing.

We smoking hopefully nowhere soft goods as compared to them I would tell him sandy.

But he is of critical importance. He said these engineered en masse.

Persist for long periods of time rules in the patients.

One node for continued antitumor activity, so having complete responses that last month or two months really provide the benefit for patients.

And as we have seen.

Several clinical programs from other sponsors.

The current approaches for allogeneic cell therapy is doing not doing that.

Consistent.

And we are really excited about the work we have been able to achieve we choose to ensure that not only we avoid graft versus host disease like others or rejection by.

Hosting.

But importantly, we absolutely rejection by natural killer cells, and we believe that that is very important.

For the lung.

Lung persistence.

We are going to be sharing more data later, this year and going into detail.

In the editing strategy and continue to share the data on the performance of the south.

So looking forward to having that conversation at that time.

Yeah.

It's Silvia and it's important to also think about the manufacture ability of this one of the things that.

Sometimes gets lost with an autologous approaches you're literally manufacturing each patient by.

One at a time, which brings tremendous cost time legs et cetera, and if youre able to manufacture for 50 to 100 people at the same time.

It just brings tremendous opportunities in terms of the efficiency cost of goods improvements that we think can ultimately expand the use of these products.

And we think with this persistence in particular.

One can achieve perhaps even better outcomes with then with the current autologous format. So that's why we're excited and we think <unk>.

Graham can move along very very quickly so from the standpoint of timelines.

Although we're not guiding yet when we look at our plans and look down the road.

Think that.

Well the Allo may start a little later I think it can finish very very quickly assuming it performs to the levels that we expect.

Thank you.

Operator?

Sure.

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

Oh, great. Thanks, so much for taking my question sorry to go back to this one but I think you mentioned a couple of times to the <unk> seven milligrams per kilogram of one milligram per kilogram, whereas indistinguishable in ctr cardiomyopathy. However, NTT are pulling their property does look to me that the one milligram per kilogram drove a better knockdown, which is obviously important to be the style.

So I'm wondering how you rationalize the difference between ctr pull neuropathy and cardiomyopathy again understand small numbers, but would love to copy your thoughts on how you rationalize that difference and then maybe on <unk> I think of your honest this shows 65% to 70% knockdown in PK Kay in the serum with their anti sense oligonucleotide wondering if that's the right bogey.

For us to keep in mind as we see your PD data.

Well with respect to the data 21, remember we get to see a lot more than you do.

So that certainly informs how we think about this stuff and David I don't know if you want to say a word or two about let me give you a little more detail about it and you could see it in our data actually if you recall when we were looking at.

Patients with Polyneuropathy patients have <unk> seven had a wide standard ever it means for their mean reduction and this is actually driven by a single patient an outlier.

We've actually not only from <unk> seven and one but also from <unk>. Three so this patient is quite different now looking at the results for cardiomyopathy with a good sample.

It looks like that is not.

At outliers as something that probably would have to be.

Looked at in terms of what's really happening in these patients. So we will continue to collect data, but it does look both based on our modeling and also on what we're seeing.

With the patients with cardiomyopathy, we do think react biologically pretty much identical to patients polyneuropathy.

GTR reduction will be the same at 701.

And I guess the other question was again, just what we're what we use as a benchmark for HCA.

Yes, the benchmark we're looking at is what packaged euro gets about a 60% reduction you'll recall in our preclinical models, we're able to get.

90% reduction so and what you've seen with GTR. So we think that we will.

Are you able to get to a good target reduction with collar crime metrics I mean, we haven't seen anything that we don't think we can meet or surpass ultimately is I guess the way to think about it.

Got it Super helpful. Also the commentary on the outlier really really helpful. Thanks, so much.

We will now begin the question and answer session.

The next question comes from Rich law with Credit Suisse. Please go ahead.

To ask a question, you may press star then one on your telephone keypad.

If you're using a speakerphone, please pick up your handset before pressing the keys.

Well hi, good morning for 2001 as you think about wishes professional studies do you think you'd need to demonstrate what the fabless showed in the label to be competitive in regards to the magnitude of benefits for the six minute walk test and I think the outcomes.

If at any time your question has been addressed and you'd like to withdraw your question, please press star then two.

And then a follow up question is that for the.

Elevated liver enzymes.

To make changes to the anti histamine Richmond as well thanks.

Yeah.

David.

<unk>.

With respect to <unk>.

How do you think about that.

Yes.

We think that that's a first point of entry that we.

I believe we are ultimately going to surpass substantially so.

So.

I mean, it's a relevant comparator out there obviously, because it's an <unk>.

Proved agent and as we've seen with others who are studying.

Different drugs in the space you have to think about what's appropriate for study design. It was appropriate for patients, but from the standpoint of improving upon any of the outcomes for Hammond is we think that the knockdown approach should be in a good position to do that.

David any other thoughts on that and with respect to that.

Pretreatment rich and any thoughts.

Repeat again, we do think that the cardiovascular events and mortality are the most important endpoints there and I think you've seen in the.

<unk> bio data the way people are doing on six minute walk as really changing over time.

The disease is better managed than it was two days with the families. So we're looking in general what we're hearing from a cardiologist or patients who are really healthy are able to work more and maybe that measure it's going to become less useful in terms of thinking about benefit real benefit is can we keep the patients out of the hospital can we keep them alive longer.

The second part.

Okay pre treatment regimen for 'twenty, one any change so yes, no. We don't think any changes are needed with that patient they came down.

Very quickly without any type of treatment. So we don't think we need to change the pre treatment.

Please limit yourself to one question and one follow-up.

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

The next question comes from Greg Harrison with Bank of America. Please go ahead.

The first question comes from June Lee with Truist.

Please go ahead.

Hi.

Hey, good morning, Thanks for taking the question.

You had mentioned advancing new platform capabilities this year.

Thanks for the updates and for taking our questions.

How do you feel about your technology toolkit, overall, and where could you add to it going forward.

What are your top one or two questions for Apollo B heading into ISA data presentation, on August 8th?

I'm assuming you plan to attend at least virtually.

Yeah.

My guess is that Laura was hoping you would ask a question like that Laura you want to give any insights into how you think about the toolkit.

Thank you.

Thanks, June. First of all, we're really excited about the outcome because we think it validates what, we've believed for a long time, which is the best way to deal with any form of amyloidosis, in particular TTR amyloidosis, is to reduce the offending protein to low levels.

We, of course, have been targeting very, very deep reductions.

Yep.

We really want to be limited by.

We think that we'll be able to take what we've already demonstrated and apply it to, patients in cardiomyopathy and would expect to see a profound clinical benefit as a result.

The gene editing modality as well if there's any read modalities, how we're investing in both fronts.

But I think, like all observers, we're interested in getting the full data set in terms of how, the patient's performed.

For in vivo in squamous extreme obligations.

Obviously, a six-minute walk test is a particular readout, but some of the harder endpoints, I think are really important to understand, which will inform how we think about studying these patients.

So yeah, we will be sharing more data when available, but we are you know.

Really leveraging a very deep and experienced team.

And I'm working very collaboratively with power takeoffs colleagues to ensure a bag of tools, we are developing research and they have.

And robust and deployable, so we cannot medicines.

I would just reemphasize the idea of tool kit the notion that you want to have.

More than one modality available to you. There is no single modality that is going to address all of the things that we pursue.

And everything that anyone is working on begins with basic CRISPR Cas biology, either from a humming point of view or for engineered proteins. So you always want to start with a deep skill in that area, which we think that we certainly accumulated.

Whether its derivative forms of that to go on and have particular use cases.

Or other approaches that.

Can be combined or.

Our goal here is to have access to all of those tools. So we.

We think about the capabilities, we want to have in terms of the particular genetic engineering problem that we want to solve and we wanted to be unlimited in that space and we think we're well on our way to being able to to make those claims.

I don't know, David, if there's anything of particular interest to you that you might, want to expand on?

Great. Thanks for taking the questions.

Yeah.

The next question comes from money, who O'hara with SBB Securities. Please go ahead.

I think a couple other things we'll be interested in, how patients did, who received the thalamus, or didn't receive the thalamus, that seemed to be part of the story.

Thanks.

As we think about the pivot to focus more on allogeneic are there.

Specific technologies investment some of the manufacturing infrastructure.

But we should think about protection and flowing through the capex any meaningful way or that infrastructure.

Infrastructure and tools they sufficiently built out that really is kind of baked into the underlying ongoing R&D spend call.

Call it a little bit on that.

Yes.

At a high level Manny.

It's an interesting thought but I don't think we're going to see a big effect from that.

What the ultimate benefit I think is going to be downstream from the patients themselves, where the reagents that they received the actual engineered so is a healthier. So that is there when you need it with a more efficient manufacturing approach in other words more.

Material produced per run.

And as lower emphasize the critical missing element, thus far and other approaches that the cells. When you put them in should persist MP essentially equivalent to what an autologous source would be but in terms of our R&D budget and the ongoing near term spend I don't think theres going to be much of an effect Glenn do you want to add any color to that.

John you've hit it I think the one thing to just to remind people listening to is we did establish a relationship with <unk> a year ago to that really had this.

This in mind that we'd be making this pivot in the future. So I think we're well established from a externalized relationship perspective on the tech upside.

That's helpful.

I did have one follow up I feel like I was missing the party if I didn't ask something about GTR.

Yes.

Obviously.

Obviously, the scale of our clinical trials is likely to perform surgery for genome editing approach, but unlikely to look like something on the scale of the tracks.

But whatever your approaches the specifics of showing an overall survival benefit.

Don't really change so do you feel compelled and the path to pursuing a possible in cardiomyopathy to do an outcome study is that even plausible for genome editing approach.

Should we expect that whatever pivotal paas and car T. J will put them out to pursue theres going to be some kind of started a clinical endpoint six minute walk et cetera.

Well I'll take a first pass at that and David is closer to the statistics and the trial design that we are.

Working through here, but.

Yeah.

I would just look to the models that are out there already for cardiomyopathy and expect that.

We will emulate a lot of that work that's been done I mean, obviously inputs that are coming for the additional information we will factor that in which gives us more confidence about event rates and the like but with respect to surrogate markers.

Our regulatory.

Approach that comes from the food and drug administration.

Other agencies around the world.

As yet that is not formally recognized as would be say cholesterol or a viral load and different.

Disease condition, so there's no doubt that.

That would certainly speed the process because GTR, so readily measured but thus far.

The stance of the regulators has been too.

It looks like those actual clinical outcomes irrespective of the PTR effect David anything.

I think those are the main points, we're seeing the on island study forever the wind to our back to figure all this out we're going to see.

The results of that and help us.

Really understand what we need to do to see.

And the biggest piece, we do think we can do better than what they did because of the, deeper reductions we get in TTR.

So, as we design our trial, that point will be important to show how we might show better, efficacy than we've seen in that trial.

Outcome study and again, we have this advantage that by getting a deeper reductions we can anticipate a better result than what they will see.

With that with any of the agents because none of them achieved type of GTR reduction that we can achieve.

Thank you.

Okay. That's helpful. Thank you.

The next question comes from Maury Raycroft with Jeffries.

The next question comes from Jay Olson with Oppenheimer.

Please go ahead.

Please go ahead.

Thank you for the update I was curious about recent publications of novel targets.

Hi, this is Ferdinand from Maury.

Just to follow up on Apollo B as well, like, how does the data inform your next steps in, the designs for the people to, like, would you rely on the six-minute walk distance as like an end point, or would you like, prefer like harder end points?

Well, as a first pass, I think the six-minute walk test has some utility, but it's really, not the most definitive end point in terms of how, I think, regulators, physicians, and even payers ultimately think about the effect of these drugs.

So for us, that's at the core of our program, but there's no doubt that six-minute walk, is a useful readout to some degree of improvement, and, you know, we think that what we've seen so far, again, is validation of the entire knockdown hypothesis for cardiomyopathy.

David, any other thoughts?

Which had been revealed from human genetics studies, showing that certain germline mutations provide protective effects against metabolic diseases and they seem to be interesting targets for gene editing are there any comments or observations you can share on those publications and as a related follow up.

What is your interest level I can tell you in pursuing a program of target's broader indications such as liver disease cardiovascular disease related to protective mutations.

But the question for you to make sure I understand your question are you asking me a germline question are you asking me about <unk>.

Somatic mutations that can have some.

Physiological benefit.

Well the specific publication I was referring to was it your mind mutation but.

You can answer the question from either perspective I suppose.

Yeah, I mean first of all from a germ line point of view, that's not something we work on.

And that was addressed some years ago as we were thinking about what was appropriate for us to work on where we could make the biggest benefit for patients and do it in a way that just.

Really perspective, where the technology is today and where we see it going.

Germline mutations manifest themselves as somatic mutations and you certainly get the readout from the fact that someone carries any genetic change and so to the extent that there's kindred search have some.

Clinical benefit which stands behind all of the genetic reasoning that's been done with some of these particular risk reduction.

Notation et cetera, we certainly look to that space as informative for relevant targets to go after but what we would ask how is that addressable episematic level as opposed to going after the germ line, so thats, where we draw the line.

Okay understood. Thank you.

The next question comes from Doug Taylor <unk> with Guggenheim. Please go ahead.

Hi, This is ray for Seth on for Doug.

Assuming an SA RNA approval in ATT RCM do you foresee challenges in enrollment and how do you think about the need or requirement from health authorities surround comparator.

David do you want to address what we saw.

Yeah, I was going to say, we've been talking for a while that we do think the most important, end points are cardiovascular events and mortality, and, you know, it was, we don't see that yet in this trial.

All of the studies that are being done currently of course don't have an active comparator and if a fire.

<unk> is approved.

Our study will likely be running before and the approval come certainly.

Yeah, certainly in Europe , as well as the U S. So we.

We do feel.

We obviously haven't talked yet exactly about what our study design is but we don't we don't know that we would need an active comparator at this point in terms of enrollment as mentioned there's enormous interest in what we're doing I think that has to do with the depth of reduction that we're going with the fact that it's a one time treatment for patients.

It's a smaller trial than some of the others.

It's also fairly short-term.

It'll be important to show that benefit by lowering TTR.

As well and those things I think will drive a lot of interest.

In our trial.

Thanks.

Thanks for that information and one follow up.

Body weight of the Piceance subject that show the day 28, and some elevation anything.

Not typical or to note for that individual.

Oh no.

We don't even know that the study drug is related I mean, it's sort of an open question at this point.

And we don't think it's related to the direct LNP infusion remember we said this is a patient who did.

Extremely well with the infusion is almost all the patients have done.

And its just finding at day 28 that was transient.

But we're just being very very thoughtful with respect to the information as we accumulate it and again it starts with the.

Substantial efficacy that we have which again as David has pointed out when you look at it seven one is we've accumulated additional patients. We just really don't see a difference between them from an efficacy point of view. So it makes the decision pretty easy.

I appreciate the input.

The next question comes from cost Us Lewis with BMO capital.

And if possible the timely.

Limit yourself to one question only possible.

Thank you.

The next question comes from Dagon Ha with Stiefel.

Please go ahead.

Hello, everyone. Thanks for taking my question I had a couple of them, but I will limit myself to one so on the leave the enzyme elevation you mentioned that these are cats.

Good morning, guys.

<unk> 28, and this is exactly when democracy boom inhibition of <unk>. So I'm wondering if.

We enjoyed a few of these kids anything to do we set very high TT, adding CBC or not months, one or two I'd probably unrelated. Thank you.

Okay, David any thoughts yet we believe these are unrelated we can't think of any connection between the PTR going down in liver function.

The enzyme stranger and of course, we have all these other patients who are equally inhibited for which there is no yeah. Yeah. So we think.

So the inhibition of the space and it wasn't really highest on the Atlas.

Yeah.

Not distinguishable.

Very helpful.

And I believe the last question then will come from Yanan, Zhu with Wells Fargo. Please go ahead.

Hi, Thanks for fitting me in I have a very very quick two part question.

<unk> T T R reduction at the 0.7 Meg per kg is skewed by the outlier could you let us know the percent reduction if that outlier. He has taken out right now I think the average 86.

If you turn to inform us on that that the percentage without the outlier and that would be great and then for the a O T elevation at around day 28 have you ruled out.

In response I E T cell, specifically a T cell response to past nine.

I know this is unlikely because here you have a transient expression, but just wanted to know if you would that help thank you.

David you want address that yes, so the percentage without the outlier would be greater than 90%.

Yeah, so it could be more detailed on that.

<unk>.

Yes.

We don't rule out a T cell or a lot of causes again.

You mentioned this is possibly related we are looking we haven't found any of the routine testing that discovered what's causing this so we don't have an answer.

Not much to add I mean at this point, we don't know.

Again, the patient asymptomatic.

Laboratory finding that disappeared quickly.

And just bear that in mind as we go as we learn more we will report on any insights that we have.

We get any.

Study progresses remember that we have a lot of patients that we've seen and the question is.

Is this just an outlier or not but obviously we are vigilant as we proceed and carry outerwear.

Thanks.

Okay.

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

Thanks for taking our questions, and congrats on all the progress.

I wanted to pivot a little bit to a different set of questions, because I'm sure you'll, get a number of other Apollo B questions.

On the HAE data expected in the second half, you outlined in the press release safety, I guess, calocrine reduction and attack rates, but heading into it, what should we think about in terms of relevant COBS?

Is it linodalumab?

Is it barotraustat or something else?

And as a follow-up, for the 2003, I didn't see any specific guidance as to when the IND, or the equivalent filing would be, as opposed to the 3001 guidance.

Great and thanks, so much for all of your great questions and for joining US today and your continued interest and support of <unk>.

So, since 2000 program is generally, I guess, has shared attributes between 2001, 2002, and now 2003, is there anything unique about the A1AT gene or the SERPINA1 gene that warrants a broader window for IND or equivalent filing?

The next question comes from Gena Wang with Barclays.

Thanks.

Please go ahead.

So, we can do the 2003 question first.

Thank you for taking my questions.

When we get to the appropriate point, we'll issue guidance as that program moves along, which is typically how we do it.

So I have one question regarding the one case of liver, enzyme elevation at a day 28.

The programs are related to each other, but they're distinct.

Can you give a little bit more color regarding how many fold of upper limit norm that reach and how long did it last?

And so, I think it's important to keep that in mind.

And since you also dosed 75 milligrams for HAE patients, do you expect similar safety profile there?

Remember that 3001 is an insertion at a different gene, at a different locus, whereas 2003 targets, the offending gene itself, SERPINA1.

And then second question regarding HAE update, you did say, you know, HAE attack rate data.

We look forward to updating everyone as we continue to progress have a great day.

So, 3001's a little bit ahead of 2003.

Just wondering if you can give a little bit more color.

They are independent programs, and we've designed them in a way that if we choose to, we can, bring them together in the same patient.

Would that be from each individual patient?

But at this point, they're separate from each other.

And what was the comparison to their baseline and say one or two months follow-up if you can give a little bit more color regarding the attack rate?

With respect to HAE, we look at the standard of care as a point of departure, and we think, that TAC0 is the relevant benchmark here. We note that there are other agents that have met similar sorts of outcomes, and all, of that is tied to the same sort of biological reasoning, which is inhibiting or reducing chelotron levels.

I think that might be four questions.

If you can inform us on that percentage without the outlier, that would be great.

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

And that's exactly the approach that we're taking.

But I tried to keep up with you.

And then for, the ALT elevation around day 28, have you ruled out an immune response, i.e.

What we've seen is that the bigger the effect, the more of a pickup you get from a clinical, endpoint point of view.

With HAE, we'll show the data that we have, which is, you know, starts with patients are at baseline and we'll give the follow-up that we have.

a T cell, specifically a T cell response to Cas9?

So, with our approach, which, you know, extrapolating from the data that we've seen with PTR already, we believe that we should be well on our way to minimally meeting the levels that they've reported out, and perhaps surpassing them, which is, of course, our objective.

And the expectation is we'll give you as much information as we have at the time.

I know this is unlikely because you have a transient expression, but just wanted to know if you ruled that out.

Great.

So the actual format of the presentation, we'll work on as we get to the point of actually doing it.

Thank you.

You may now disconnect.

Thanks so much.

But as I think you know, it's been our principle to try to be as transparent as possible.

David, do you want to address that?

And I would expect that the general approach would be very, very similar to what you've seen with TTR because the programs are so related.

Yeah.

With respect to the one patient in the 2001 program, we'll go through the information that we have when we do a data disclosure later this year. But I just emphasize that as we've shared in our script, the patient did extremely well.

So the percentage without the outlier would be greater than 90%.

It's, entirely asymptomatic.

Yeah.

It's a laboratory abnormality that was transient in nature.

So there'll be more details on that.

But because we believe we have so much room on the efficacy side, that backing off the dose, is a reasonable thing to do, particularly since our database has grown. We've seen that it's essentially indistinguishable TTR reduction levels between the 0.7 and 1.0 milligram.

Yeah.

[music].

Remember that when we did some of our first dose selections, it was based on essentially three, people. And as we said all along, as we do our phase one dose finding work, information will accumulate that will influence our thinking.

You can't, we can't, we don't rule out a T cell.

And we've been very gratified with the outstanding safety profile and the continuing excellent TTR performance of the drug.

There are a lot of causes.

I don't know, David, is there anything else you want to provide?

Again, we mentioned it's just possibly related.

I think a few other questions are in there.

We are looking.

For, the HAE patients, there have been no liver enzyme elevations and the safety has been outstanding there.

We haven't found any of the routine testing that discovered what's causing this.

In terms of the attack rate, just to give a little more detail there, we will be looking at individual patients in that analysis.

So we don't have an answer.

And the main way this is done is by doing a run-in analysis, how many events are there before they get treated and then looking at how many events there are after that. And it is usually over a period of two to four months, depending on the follow-up.

Not much to add.

I guess just one other thought on the patient you asked about, Gena, is that remember that day 28, yeah, one of the things that is important to think about with LNPs is as a class, you know, we certainly look a lot like the class, LFP elevations, when they occur, tend to be right around the time of dosing, which is day 1, 2, or 3.

I mean, at this point, we don't know.

We've seen very low elevations, which we reported on.

Again, the patient, asymptomatic, it was a laboratory finding that disappeared quickly.

This is a transient finding out weeks later, which we have no idea if it's even related to the drug, although we've considered that it may be possibly so, and again, it was transient in nature.

And just bear that in mind as we go.

So, again, just thinking about the bigger picture here and choosing the right dose that balances what we're trying to achieve, we think we've got lots of room to go on the efficacy side.

As we learn more, I mean, we'll report on any insights that we have, if we get any, as the study progresses.

Thank you very much.

Remember that we have a lot of patients now that we've seen, and the question is, is this just an outlier or not?

Sure.

But obviously we're vigilant as we proceed and carry out our work.

The next question comes from Joseph Thorn with Cohen and Company.

Thanks.

Please go ahead.

This concludes our question and answer session.

Hi, Eric.

I would like to turn the conference back over

Good morning.

to Ian Karp for any closing remarks.

And thank you for taking my question.

Great.

Just in terms of the flip for 5001 over to Aloe, maybe when will that be in a place to move into the clinic?

And thanks so much for all of your great questions and for joining us today and your continued interest and support of Intelia.

Is that going to be a nearest term milestone?

We look forward to updating everyone as we continue to progress.

And maybe how would that relate to when 6001 could enter clinical development?

Have a great day.

© BF-WATCH TV 2021

Thank you.

The conference has now concluded.

Thanks for the question.

Thank you for attending today's presentation.

We haven't guided to a particular date yet.

Remember what we've said, which is the next incarnation of this will be with the same T cell receptor.

Yeah.

So we remain absolutely excited about looking at T cell receptor biology, the WT1 target, et cetera.

And remember that behind all this is the logic that while CAR T's certainly have their place and performed well, we have our own CAR T programs, we believe the larger opportunity with cell-based therapy for cancer is with other formats.

[music].

In TCR, we think it's the most promising one of those.

So with respect to moving forward, we've got many of the innards in place, if you will, and it's really adapting our Allogeneic platform, which we're incredibly excited about, to that.

So as we finalize those steps, we'll share that with upcoming updates and look forward to telling you more about that at that time.

Great.

And maybe just a quick follow-up on 501.

Are you going to present any of the data from the auto program if you dose any patients there?

We'll look at what we get.

I mean, we're certainly following patients we've dosed.

Remember that we are not making the switch based on any efficacy or safety readout.

This is really just based on the merits of what we think is an Allo approach, as Laura laid out.

You get better cells faster that we think are going to just be superior in performance to anything that an autologous format would be able to provide.

But as we collect information and think about future updates, particularly in the context of the Allo program, we'll think about that and ensure it as we see appropriate.

Great.

Thank you very much.

The next question comes from Swatneel Malikar with Piper Sandler.

Please go ahead.

Thank you for taking my questions.

So I guess a couple of them.

One on HAE program.

So given that there were some regulatory concerns during Tag Zero approval related to chronic suppression of the calicrine pathway, what has been the regulatory feedback on this program and are there any additional safety monitoring requirements for the 2002 program?

And then I will follow up.

HAE is moving very briskly.

All of our regulatory interactions have been pretty straightforward, but David, I don't know if there's any additional color you want to share.

I would say in multiple nationalities, we've had good feedback on what we're doing.

They're happy with the safety program that we've put in place.

And as we've just alluded to, you'll see the data later this year, but are also pleased with the safety we're seeing.

And then for the fixed dosing regimen of 0.7 mg per kg equivalent, it looks like safety and liver enzyme elevation was one of the key reasons to pursue that.

So the question that I have is, of the total 30 patients that are dosed to date, is there any other patients who had any ALT or liver enzyme elevations, even if not significant, like any minor or incremental elevations?

Well, you've seen some of the data that we've presented.

Certainly around the time of infusion, you'll get very low-level increases in LFTs, and we've presented that information.

At the last easel presentation, I think there was an example of one patient who had just an excursion just outside the limits of normal at day 28.

So yes, in that sense, there's other examples.

All right.

Thank you.

The next question comes from Salveen Richter with Goldman Sachs.

Please go ahead.

Separately, on the switch to allogeneic for your AML program, could you just expand on the rationale here, both behind pursuing a better product and your understanding of construct here?

I'm just trying to get a sense of the foundational work on the allogeneic side.

So maybe David can say a word about any impact, if any, to the timeline.

And then I'll have Laura take you through the thinking on the Allo and why we're so excited about it.

But David, how about you first?

So let me take you back to really easel where we showed 15 patients from the polyneuropathy program.

And what we saw there was deep reductions, really starting at 0.3 is where we see it, durable and up through 1 milligram.

At that point, it looked like the 1 milligram was slightly better than the 0.7 and went forward with that.

As we've said now, we have more than 30 patients.

We have really multiples of the number of patients at 0.7.

So that with this increased data, it's quite clear that the efficacy at 0.7 and 1 are really indistinguishable.

So with that, now that we've, and you see the rate of enrollment at this point, the investigators are really excited about the program, doing very well.

So we have a lot of information on patient cardiomyopathy, and what we do going forward, we'll still be able to enroll all the patients by the end of the year as we've guided from everything we see.

And that has to do with the, how much we've learned.

And recall it, with the cardiomyopathy patients, we did study both .7 and 1 in order to pin down this question.

In drug development, you really want to go with the lowest dose that gives you that efficacy.

What we're seeing in this program is a very flat dose response curve.

Laura, you want to talk about the ELO platform a little bit, and how we think about it, and why we're pivoting?

Sure.

Yeah, no, no, happy to do that.

So, you know, what we've learned from our study, but importantly for others, is that, you know, the importance of an ELOgen-A platform is not only to have a consistent cell product with high quality, you know, patient manufacturing, you know, resulting also in lower cost of goods as compared to an autologous therapy.

But what is of critical importance is that these engineered ELO cells must persist for long periods of time in the patients to allow for continued anti-tumor activity.

So, having, you know, complete responses that last, you know, a month or two months don't really provide the benefit we want for patients.

And as we have seen with, you know, several clinical programs from other sponsors, the current approaches for ELOgen-A cell therapies do not bring that persistence.

And we are really excited about what we have been able to achieve, which is to ensure that not only we avoid graft-versus-host disease, like others, or rejection by host T cells, but importantly, we avoid rejection by natural killer cells.

And we believe that that is very important for this long, long persistence.

We are going to be sharing more data later this year, going into detail in the actual editing strategy and continue to share data on the performance of the cells.

So, looking forward to having that conversation at that time.

You know, it's something that's important to also think about the manufacturability of this.

One of the things that sometimes gets lost with an autologous approach is you're literally manufacturing each patient by, you know, one at a time, which brings tremendous cost, time lags, et cetera. And if you're able to manufacture for 50 to 100 people at the same time, that just brings tremendous opportunities in terms of efficiency, cost of goods improvements that we think can ultimately expand the use of these products.

And we think with this persistence in particular, one can achieve perhaps even better outcomes than with the current autologous format.

So, that's why we're excited, and we think that the program can move along very, very quickly.

So, from the standpoint of timelines, although we're not guiding yet, when we look at our plans and look down the road, I think that, well, ALO may start a little later.

I think it can finish very, very quickly, assuming it performs to the levels that we expect.

Thank you.

Sure.

The next question comes from Luca Issi with RBC.

Please go ahead.

Oh, great.

Thanks so much for taking my question.

Sorry to go back to this one, but I think you mentioned a couple of times that the 0.7 mg per kg and 1 mg per kg were indistinguishable in TTR cardiomyopathy.

However, in TTR poloneuropathy, it does look to me that the 1 mg per kg drove a better knockdown, which is obviously important to be the silencers.

So, wondering how you rationalize the difference between TTR poloneuropathy and cardiomyopathy.

Again, I understand small numbers, but would love to kind of hear your thoughts on how you rationalize that difference.

And then maybe on HAE, I think Ionis has shown 65 to 70 percent knockdown in PKK in the serum with their antisense oligonucleotide.

Wondering if that's the right bogey for us to keep in mind as we see your PD data.

Well, with respect to the data on 21, remember, we get to see a lot more than you do, and so that certainly informs how we think about this stuff.

And David, I don't know if you want to say a word or two about it.

Let me give you a little more detail about it.

And you can see it in our data, actually.

If you recall, when we were looking at the patients with poloneuropathy, the patients at 0.7 had a wide standard average mean for their mean reduction.

And this is actually driven by a single patient, an outlier, who's actually an outlier not only from 0.7 and 1, but also from 0.3.

So this patient is quite different.

Now, looking at the results for cardiomyopathy with a good sample, it looks like that outlier is something that probably would have to be not looked at in terms of what's really happening in these patients.

So we will continue to collect data, but it does look both based on our modeling and also on what we're seeing with the patients with cardiomyopathy.

We do think we act biologically pretty much identical to patients with poloneuropathy, that the TTR reduction will be the same at 0.7 and 1.

I guess the other question was, again, just what we use as a benchmark for HAE.

Yeah, the benchmark we're looking at is what type 0 gets about a 60% reduction.

If you recall, in our preclinical models, we're able to get a 90% reduction, and what you've seen with TTR. So we think that we will be able to get to a good target reduction with calocrine and that stuff.

I mean, we haven't seen anything that we don't think we can beat or surpass, ultimately, is, I guess, the way to think about it.

Got it.

Super helpful.

Also, the commentary on the outlier, really, really helpful.

Thanks so much.

The next question comes from Rich Law with Credit Suisse.

Please go ahead.

Hi, good morning.

For 2001, as you think about registrational studies, do you think you need to demonstrate what the families showed in this label to be competitive in regards to the magnitude of benefits for the six-minute walk test and the safety outcomes?

And then a follow-up question is that for the elevated liver enzyme, are you looking to make changes to the steroid and antihistamine regimen as well?

Thanks.

David, with respect to kafametus, how do you think about that?

You know, I mean, we think that that's...

I think that's a first point of entry that we believe we're ultimately going to surpass substantially.

And so, I mean, it's a relevant comparator out there, obviously, because it's an approved agent.

And as we've seen with others who are studying different drugs in the space, you have to think about what's appropriate for study design and what's appropriate for patients.

But from the standpoint of improving upon any of the outcomes for hamatos, we think that the knockdown approach should be in a good position to do that.

David, any other thoughts on that with respect to the pretreatment regimen?

Any thoughts?

Right.

Just to repeat again, we do think that the cardiovascular events and mortality are the most important endpoints there.

And I think you've seen in the BRIDGE bio data that the way people are doing on a six-minute walk is really changing over time.

You know, the disease is better managed than it was in the days of tefamidus.

So we're looking in general, what we're hearing from a cardiologist, are patients who are really healthier, able to walk more, and maybe that measure is going to become less useful in terms of thinking about benefit.

But the real benefit is, can we keep the patients out of the hospital?

Can we keep them alive longer?

The second part… The pretreatment regimen for 21, any changes?

Oh, yeah.

No, we don't think any changes are needed.

You know, with that patient, they came down very quickly without any type of treatment.

So we don't think we need to change the pretreatment.

The next question comes from Greg Harrison with Bank of America.

Please go ahead.

Hey, good morning.

Thanks for taking the question.

You've mentioned advancing new platform capabilities this year.

How do you feel about your technology toolkit overall, and where could you add to it going forward?

My guess is that Laura was hoping you would ask a question like that.

Laura, do you want to give any insights into how you think about the toolkit?

Yeah.

So we really want to be unlimited by the gene editing modality as well as the delivery modality.

So we're investing in both fronts for in vivo as well as ex vivo applications.

So, yeah, we will be sharing more data when available.

But, you know, we are really leveraging a very deep experience team, and working very collaboratively with our tech ops colleagues to ensure that, you know, tools we develop in research, they have to be robust and deployable so we can actually make medicines out of them.

I would just reemphasize the idea of toolkit, the notion that you want to have more than one modality available to you.

There's no single modality that's going to address all of the things that we pursue.

And everything that anyone is working on begins with basic CRISPR-Cas biology, either from a homing point of view or for engineered proteins.

And so you always want to start with a deep skill in that area, which we think that we certainly accumulated.

But whether it's derivative forms of that that go on and have particular use cases, or other approaches that can be combined, our goal here is to have access to all of those tools.

So we think about the capabilities we want to have in terms of the particular genetic engineering problem, that we want to solve, and we want to be unlimited in that space.

And we think we're well on our way to being able to make those claims.

Great.

Thanks for taking the question.

The next question comes from Mani Foroohar with SVB Securities.

Please go ahead.

Thanks for taking the question.

I was thinking about the pivot to focus more on Allogeneic.

Are there specific technologies, investments, some of the manufacturing infrastructure, that we should think about potentially flowing through to CapEx in a meaningful way?

Or is that infrastructure and tools that you've sufficiently built out that really is kind of baked, into the underlying ongoing R&D spend?

Could you comment a little bit on that?

Just at a high level, Mani, it's an interesting thought.

But I don't think we're going to see a big effect from that. But the ultimate benefit, I think, is going to be downstream for the patients themselves, where the reagent that they receive, the actual engineered cell, is a healthier cell that is there when you need it with a more efficient manufacturing approach. In other words, more material produced per run.

And as Laura emphasized, the critical missing element thus far and other approaches, that the cells, when you put them in, should persist and be essentially equivalent to what an autologous source would be.

But in terms of our R&D budget and the ongoing near-term spend, I don't think there's going to be much of an effect.

Glenn, do you want to add any color to that?

No, John, you've hit it.

I think the one thing just to remind people listening, too, is we did establish a relationship, with CellX a year ago, too, that really had this in mind that we'd be making this pivot in the future.

So I think we're well-established from an externalized relationship perspective on the tech-op side.

That's helpful.

I'd have one follow-up.

I feel like I was missing the party if I didn't ask something about TTR.

Obviously, the scale of a clinical trial that's likely to perform for a genome editing approach is unlikely to look, like something on the scale of a tract.

But whatever your approach is, the statistics of showing an overall survival benefit don't really change.

So do you feel compelled in pursuing a path to proven cardiomyopathy to do an outcome study?

Is that even plausible for a genome editing approach?

Or should we expect that whatever pivotal path in TTR cardiomyopathy you pursue is going to be some kind of, surrogate clinical endpoint, six-minute walk, et cetera?

Well, I'll take a first pass at that.

And David is closer to the statistics and the trial design that we're working through here.

But I would just look to the models that are out there already for cardiomyopathy and expect that we will emulate a, lot of that work that's been done.

I mean, obviously, inputs that are coming for the additional information will factor that in, which gives us, more confidence about event rates and the like.

But with respect to surrogate markers, that's a regulatory.

There's no doubt that that would certainly speed the process because TTR is so readily measured, but thus far, the stance of the regulators has been in favor of TTR.

We're going to see the results of that and help us really understand what we need to do to speed up the process.

Again, we have this advantage that by getting a deeper reduction, we can anticipate a better result than what they'll see with any of the agents because none of them achieve the type of TTR reduction that we can achieve.

Okay, that's helpful.

Thank you.

The next question comes from Jay Olson with Oppenheimer.

Please go ahead.

Thank you for the update.

I was curious about recent publications of novel targets which have been revealed from human genetic studies showing that certain germline mutations provide protective effects against metabolic diseases. They seem to be interesting targets for gene editing.

Are there any comments or observations you could share on those publications?

As a related follow-up, what is your interest level at Intellia in pursuing a program that targets broader indications such as liver disease or cardiovascular disease related to protective mutations?

I have a question for you to make sure I understand your question.

Are you asking me a germline question or are you asking me about somatic mutations that can have some physiological benefit?

Well, the specific publication I was referring to was a germline mutation, but you can answer the question from either perspective, I suppose.

Yeah, I mean, first of all, from a germline point of view, that's not something we work on.

That was addressed some years ago as we were thinking about what was appropriate for us to work on where we could make the biggest benefit for patients and do it in a way that just really respected where the technology is today and where we see it going.

But germline mutations manifest themselves as somatic mutations, and you certainly get the readout from the fact that someone carries any genetic change.

And so to the extent that there's kindreds that have some clinical benefit, which stands behind all of the genetic reasoning that's been done with some of these particular risk reduction mutations, etc., we certainly look to that space as informative for relevant targets to go after.

But what we would ask now is, is that addressable at the somatic level as opposed to going after the germline level?

So that's where we draw the line.

Okay, understood, thank you.

The next question comes from Debjit Chattopadhyay with Guggenheim.

Please go ahead.

Hi, this is Ry Forseth, I'm for Debjit, assuming an SIR&A approval in ATTR-CM, do you foresee, challenges in enrollment and how do you think about the need or requirement from health authorities around a comparator?

David, do you want to address that?

Yeah, what we see, you know, all the studies that are being done currently, of course, don't have an active comparator and if a fire answer is approved, our study will likely be running before any approval comes, certainly, you know, certainly in Europe as well as the, U.S. We do feel, you know, we obviously haven't talked yet exactly about what our study design, is but we don't need, we don't know that we would need an active comparator at this point.

In terms of enrollment, as we've mentioned, there's enormous interest in what we're doing, I think that has to do with the depth of reduction that we're going with the fact that it's a one-time treatment for patients as well and those things, I think, will drive a lot of interest in our trial.

Thanks for that information and one follow-up.

The body weight of the PN subject that showed the day 28 enzyme elevation, anything not, typical or to note for that individual?

No.

We don't even know that the study drug is related.

It's sort of an open question at this point and we don't think it's related to the direct, LNP infusion.

Remember, as we said, this is a patient who did extremely well with the infusion as almost, all the patients have done and it's this finding at day 28 that was transient but we're just being very, very thoughtful with respect to the information as we accumulate it and, again, that starts with the substantial efficacy that we have, which, again, as David has pointed out, when you look at it, 0.71 as we've accumulated additional patients, we just really don't see a difference between them from an efficacy point of view.

So it makes the decision pretty easy.

Appreciate the input.

The next question comes from Kostos Elouris with BMO Capital and, if possible, to kindly

limit yourself to one question only, if possible.

Thank you.

Hello, everyone.

Thanks for taking my question.

I had a couple of them but I will limit myself to one.

So on the liver enzyme elevation, you mentioned that these occurred at day 28 and this is, exactly when the maximum inhibition of TTR is reached.

So I'm wondering if, in your view, this has anything to do with very high TTR inhibition, at month one or the two are probably unrelated.

Thank you.

David, any thoughts?

Yeah, we believe these are unrelated.

We can't think of any connection, between the TTR going down and liver function changing, the enzymes changing.

And of course we have all these other patients who are equally inhibited for which there's no... Yeah.

So the inhibition of this patient wasn't really higher than the others?

No, not distinguishable.

And I believe the last question then will come from Yanan Zhu with Wells Fargo.

Please go ahead.

Hi, thanks for fitting me in.

I have a very, very quick two-part question.

You mentioned

that TTR reduction at the 0.7 mg per kg is skewed by outlier.

Could you let us know the percent reduction if that outlier is taken out?

Right now it's, I think, the average 86.