Q2 2023 Intellia Therapeutics Inc Earnings Call

Good morning, and welcome to the <unk> Therapeutics second quarter 2023 earnings call Earnings Conference call. My name is drew and I will be your conference operator today. Following formal remarks, we will open the call up for a question and answer session.

This conference is being recorded at the company's request and will be available on the company's website. Following the end of the call. As a reminder, all participants are currently in listen only mode. If anyone requires operator assistance during the conference. Please press star zero on your telephone keypad.

I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and corporate Communications I didn't totally please proceed.

Thank you operator, and good morning, everyone welcome to <unk> Therapeutics second quarter 2023 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 intaglio, TX Dot com.

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

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

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

Joining me from Intel you are Dr. John Leonard Chief Executive Officer, Dr. David Lebel, Chief Medical Officer, Dr. Laura Sepp Lorenzi, 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. Laura will review, our R&D progress and Glenn will review <unk> financial results for the second quarter 2023, before we open up the call for your Q&A.

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

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

We're leading the genome editing resolution broadest and deepest toolbox.

Novel editing and delivery solutions 2023 continues to be another year of important progress across our clinical pipeline and differentiate genome editing platform.

Particularly pleased with the significant advancement of our two lead clinical programs not only are these two programs potentially paradigm shifting treatments for patients with <unk> amyloidosis nature E, but our success and learnings these investigational therapies.

<unk> set the foundation for our broader long term goals and strategic priorities.

Within Chile, 20 O two in development for the treatment of predatory angioedema.

We announced that in just a handful of months, we were able to identify all patients required to fully enroll the ongoing phase II portion of the study.

Notably, we now expect to initiate the phase III program as early as the third quarter of next year subject to regulatory feedback.

In addition to the exceptional clinical development execution and recent positive data update for until late 'twenty. Two we're getting very close to submitting our second in vivo <unk> application.

This next IND submission expected in September will support the planned pivotal trials until late 20th one for people with cardiomyopathy manifestation of <unk> amyloidosis.

Estimates indicate that maybe as many as 500000 people around the world who suffer from this disease.

Subject to regulatory feedback, we expect to initiate a global phase III by year end.

We believe all of this progress positions us well to deliver on initiating pivotal studies for both programs a core strategic priority over this year and next.

Lastly, I'd like to take this opportunity to thank John Prince swap Formula one of our founding board members, who retired from our board in June Yes.

<unk> vision and leadership over the past decade have been integral to our growth and recent achievements.

Ill now hand, the call over to our Chief Medical Officer, David Loeb.

Who will review the lead clinical programs in greater detail.

David.

Thanks, John and welcome everyone.

I'll begin with 'twenty, one our in vivo CRISPR based candidates with the potential to halt and reverse disease in people living with H T. T. R. Amyloidosis after a single dose.

Or a T T R. P M.

Distant with our prior guidance for a mid year submission. We are on track to submit an NDA application in September for a global pivotal study of 'twenty one.

We are in the final stages of preparing the comprehensive I N D package and expect to initiate the study by year end subject to regulatory feedback.

For hereditary H T. T. R. P. M. We are continuing to make steady progress with the preparations for a phase III study.

Looking ahead, we plan to present additional data from both arms of the ongoing study later this year.

Moving to 20 O two in development for HIV.

We have been really pleased with the interest and enthusiasm for the 20th two program from investigators and patients alike. Both in the U S and internationally.

The updated phase one data presented in June has fueled this enthusiasm even further.

Across all 10 patients.

95% mean reduction in monthly attack rate was observed after a single dose of 20 O two through the latest follow up.

The medium duration of follow up was nine months.

At all three dose levels 20 O two has been well tolerated and any adverse events were grade one or two in severity.

Yeah.

Earlier. This morning, we announced that we have identified all patients needed to complete enrollment in the phase two portion of the study.

Based on the high level of interest for 20 O. Two all slots had been allocated to current ex U S sites.

Other sites planned for phase two including U S sites will now be part of the planned phase three study.

Yeah.

Following the clearance of our I N D received requests from the FDA to provide supplemental preclinical data related to the inclusion of female patients of childbearing potential.

While we could have proceeded with enrolling U S patients outside of the subgroup with a protocol amendment. The study was already rapidly enrolling at ex U S sites and soon to finish.

After discussion with the FDA, we have come to an agreement on the design of our reproductive study in mice to supplement the data that we have already supplied in our initial NDA submission.

Such data are often required as part of a Registrational program and we will now be submitted along with additional data being generated in advance of the initiation of the phase III study.

The main objective of the phase two is to confirm the optimal dose for phase III.

By enrolling a diverse patient population ex U S <unk>.

Women of childbearing potential.

We're in a great position to move forward to do just that.

Further we announced today that we now expect to begin the phase III study as early as the third quarter of 2024 subject to regulatory feedback.

We are full steam ahead and look forward to updating you on our progress for initiating the 20 O two global pivotal study.

I'll now hand, the call over to Laura our Chief Scientific Officer, who will provide an update on our R&D efforts.

Thank you David beyond our lead programs, we're advancing a pipeline of in vivo and ex vivo programs towards the clinic for MTA like Turkey and won our first wholly owned in vivo infection program. We continue have to come back I N DNA lean activities and plan to submit a CPA, but yeah.

We're excited to be moving this program into the clinic for a number of reasons first there are few effective therapeutic options for patients suffering from outside of London. They take some efficiency frequently they really they deemed unsafe M D C.

Based on our preclinical work, we believe M. D. L. A circa one can normalize I called one levels for patients. Following a single dose. Additionally, NPA later get one will be in caveats first gene mutation program to enter the clinic.

Successful, we believe we can apply these modular approach to a host of these pieces called Bangor, Michigan functional protein where do these high unmet need we look forward to updating you on our progress across our I O M. B platform more broadly as we move through the second half of a year.

I'll now hand over the call to Glenn our Chief Financial Officer, who will provide an overview of our second quarter 2020 financial results.

Thank you Laura good morning, everyone and tell you continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform.

Our cash cash equivalents in marketable securities were $1 $1 billion as of June 32023.

Two $1.3 billion as of December 31, 2022.

The decrease was driven by cash used to fund operations of approximately $227 $3 million.

The decrease was offset in part by $24.6 million of interest income.

$8 million of collaborator reimbursements.

$3.3 million and proceeds from employee based stock plans.

$1.5 million of net equity proceeds from the company's at the market program.

Our collaboration revenue decreased by <unk> $4 million to $13 $6 million during the second quarter of 2023.

Compared to $14 million during the second quarter of 2022.

R&D expenses increased by $25 $1 million to $115 $3 million during the second quarter of 2023.

Compared to $90 $2 million during the second quarter of 2022.

The increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs.

Stock based compensation included in R&D expenses was $22 $4 million for the second quarter of 2023.

G&A expenses increased by $8 $5 million to $30 $7 million during the second quarter of 2023.

Compared to $22 $1 million during the second quarter of 'twenty two.

This increase was primarily related to an increase in stock based compensation of $5 $1 million.

Stock based compensation included in G&A expenses was $14 million for the second quarter of 2023.

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

There's certainly been a very productive first half of the year, we have a number of additional milestones still to come in the months ahead.

With that we will now open the call for your questions. Operator, you May now open the call for Q&A.

We will now begin the question and answer session.

I'll ask a question you May press Star then one on your Touchtone phone, if you're using a speakerphone. Please pick up your handset before pressing the keys to withdraw your question. Please press Star then two.

He used limit yourself to one question.

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

The first question comes from Maury Raycroft with Jefferies.

Please go ahead.

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

I'm really not true from what we see in their overall results, we do need to see the details of what they have and that will be coming up those details are gonna be very helpful to us in the design of our trial, we'll know more about event rates will know about more about the status of patients.

Ah the drug itself. The the bridge by out compound is obviously very similar to feminists. It works by a different mechanism and we do think that these are likely not as good as reducing T. T. R. As you know we've been able to get to very low levels of of T. T. R.

So kind of you know so we we use all the information coming from this as well as later studies. Besides the trial, but we do think it'll be about the size of pretty similar to the on the island trial too to Helios.

The next question comes from looked at E C with RBC capital. Please go ahead [noise].

Hi, This is rena on fairly bad things for instance.

Just wanted to ask could you remind us what the latest thinking is on Jean editing outside to let their call and I think he showed us some tantalizing data last year for any of the editing M. C. D 34.

He was still thinks doesn't sound. So I'm wondering if you had any update there.

Generally speaking I can tell you that we continue to work very very hard moving Ah in vivo editing outside the liver.

You're right, we presented some really encouraging data, particularly with respect to collect stem cells thinking down the road in terms of things like sickle cell disease et cetera, where you know the preferred approach would be not to do a moment transplant, but to actually use an L. M. P. P.

[noise] approach to avoid the morbidity that typically accompany supplemental transferred we continue to do that work.

I will say that.

Pursuing a variety of different modality set a target even beyond Hse's and has been typical for us in the past as we think that we have a body of work that is ready to be presented scientifically we will share that but rest assured ah there's there's more to come.

The next question.

The next question comes from Joseph Thorne with T. D. Cohen. Please go ahead.

Hi, there good morning, and thank you for taking my question, maybe just one on the additional data for the woman of Childbearing age I guess was there anything that spurred this asked by the F. D. A and then as you think about it it's like ability to your other programs. Obviously T. T. R. C. M is you know more predominately a mail.

Ordering an older patients I guess is there any applications for this for the upcoming 90 submission. Thank you.

[noise], there's there's no safety data that's provoke this particular request of the extensive work that we supplied them and the I D, which includes a very large breeding studies in a careful analysis of that data we've looked at germs.

Germline cells, specifically, we know that they are unaffected. Our view is that this is the F. D. A taking very considered view of the space and looking for us.

Fill out what is a typical setup data that usually supplied a little later in the program, but from the standpoint of of the study itself. This is something that is commonly done no clinical data et cetera is appeared that speaks to this at all and we're well on our way to completing the work is.

Applying it to the F D. A so we can get on with the study of sweetness, we said.

I guess I'm, sorry, before I forget you you asked about implications with respect to 20 O. One at this point, we don't see that and certainly your point of when you look at the demography of that disease Ah Ah. It's typically a patient sort of patients that are older bye.

As to men in general and so we just don't see it playing out in any really fundamental way with respect to the program.

Alright, Thank you sure.

Sure.

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

Hey, Good morning. This is Mary <unk>, Okay, great. Thank you so much for taking our questions I take care of the interest from the H a D program I guess looking at your other programs that feedback have you received from physician and patient I'm a P. T R programs ongoing.

Maybe David you can speak to your interactions that are becoming pretty extensive at this point what are what are you learning yeah. Thanks, Yeah. The the biggest group that we hear from of course as investigators who were in touch with around the World I would say, we talk with every investigator who treats patients at a debating centers with this disease.

And and there there is a lot of excitement we we do know.

Most of those fights or maybe all those sites will end up joining the study and as you've seen in some of the other studies. This study's do enroll quite briskly and if it really is increasing population of patients with ATT or how do I do.

<unk> and cardiomyopathy.

We also we hear about patients through through some of these physicians excitement. That's their reactor are starting to hear directly from patient people trying to get into studies.

Of course, we want we want to satisfy that made it possible so where.

You know, we're working to get to the phase three study opened as as quickly as possible and estimated to be at the end of this year.

The next question comes from June Lee with <unk> Securities. Please go ahead.

Hi, good morning, and thanks for taking <unk> for June So earlier this year <unk> subjects here on in <unk> Phase two study.

Very high 90 per cent reduction in Z E T, but the impact on liver fibrosis improvements still unclear I'm Takeda is doing phase three study with Hunter 60 patients. So could you. Please elaborate on your plans and <unk>.

Spectation score at N T L E 203. Thanks.

David any thoughts in terms of how other data is affecting her thinking for 20th three yeah. We we've been encouraged by the data that we're seeing coming from the Qaeda studies and we do think it's.

Obviously, it's not a phase III definitive study, but he was very supportive of the benefit of reducing the the mutant protein and and the benefit for the liver. So we are for that program completing our Andy enabling studies this year and we'll be talking soon about when that will be getting into the clinic.

Thanks.

[noise]. The next question comes from Gina Wang with Barclays. Please go ahead.

Hi, Good morning. This is hershey it on for Gina. Thank you for taking our questions.

Quick clarification I think you covered this end up I'm prepared remarks, and I just wanted to confirm it's not right for Tuesday are there are two you've identified all the patience and faith too and all of the patients in the study will be enrolled X U S and Europe , you'll be waiting till the phase three to enroll a U S.

Patience can you <unk>.

If I again, what's the reason for this and why you're waiting to Unreal you.

U S patients and faithfully it not and paste it right now.

Thank you thank.

Thank you you're correct that the study is fully enrolled Ah we've identified all the patients as we said the study has been moving extremely quickly as you can see I mean, we'd be enrolling patients just in March of this year and here we are at the very beginning of.

Of August and we've identified all of the patients and then some to come into the trial. So this is one of those things that's moved very very aggressively and we're excited about that and what that means.

By the way that it same enthusiasm is reflected with U S investigators in patients who contact us.

The reason.

Reason for the particular choice was with the feedback from the F. D. A after the successful clearance of the I D to complete the work that we would have needed to do to allow women of childbearing potential in the U S. You remember where enrolling women of childbearing potential in every site every country outside the.

U S. We would have a delayed the study substantially and given that the objective of the program is to capture the demographics, which were doing range of different disease States range of ages women of childbearing potential not in men et cetera.

We were accomplishing that especially with the primary goal of identifying the dose to take into phase three so rather than a delay the idea was to complete the work submit that to the F. D. A and bring you as a patient since this study in phase three by the way there are many U S sites, who wanted to.

And given again the rep rapidity of the enrollment they weren't able to come online fast enough anyway. So we think we can be very well situated in the U S. We will have an abundance of U S patients.

Think we'll be well prepared to begin to phase III program potentially as early as the third quarter of next year and that's what we're working towards.

The next question comes from the <unk>.

<unk> with Guggenheim partners.

Please go ahead.

Good morning, and thanks for taking my question.

But Tuesday at one two or 2001 do you think I'm bad 90 per cent T. T M knocked down on a very tight control that you'll have over the D. T R.

Will that translate into survival advantage and could you remind us where you stand with respect to manufacturing as you prep for two phase three studies over the next 12 months.

Well I'll have David address why we're excited about as you pointed out the very very deep reductions and critically for the study the very low variance that we see across all of the patients treated so far we're quite convinced that that's gonna be a meaningful advantage for patients.

But with respect to phase III readiness, we put a lot of work into preparing for that int that will enable that phase III program and your point about having commercial material readiness as one carry southeast phase three trials is a really important observation. So the idea is.

You know to complete this trial get the results that we're looking for have the final material in the study and be in a position that when we achieve Ah approval for the product to move forward as quickly as possible to the marketplace and we've always been shooting ahead of the doctors so to speak and and this is very much a part of.

Hello, I've been thinking about it.

If you have something to add with respect to keep your levels and how that translates into clinical benefit.

Yeah, we we do believe that these deep reductions were getting not only being at the 90% in greater range, but also having the great consistency means that we can we have the potential benefit all patients there aren't patients who were having lesser amounts you know when you have an average of 80 per cent with other agents have the patience.

Less than 80 per cent reduction so that that's very important.

The other thing we're we're learning in terms of survival advantage I think is what we've seen in the bridge Bios study, we've talked a lot about how we don't think the six minute walk is a great pets and in fact, they they they're studying failed on that test.

What we're seeing is that you do need a longer period to see the benefit of these agents and we do things by having a large study with long follow up we will come out positive on the most important and points that will include cardiovascular events in in mortality. That's what we're looking forward to in our phase III study.

The next question comes from young on Jew with Wells Fargo Securities. Please.

Please go ahead.

Thanks take further questions what would be the timeline for completing the supplemental preclinical data that that he.

F D. A has agreed upon about the design us and do you think.

Do you plan to collect certain data from the female patients of childbearing age in the upcoming phase two study and if so what might those.

Those data points b. Thanks.

Well the particular studies that we're doing our an abbreviated form of water. A typical studies that look at embryological development that will be done well in advance of what would be the earliest phase three study start for us, which I said earlier it could be.

As early as a three quarter with respect that precise month and all that it. It's just not gonna have an effect in terms of how the program proceeds. So I think we're well on our way David anything different that we're doing for collecting patient and women.

Yeah. There's nothing you know they've got the same complete data collection that other patients cat.

Look at all patients we look at studies by gender and other things to see if there's any different from the effects. We don't expect to see any difference between males and females older or younger women of.

Of course, another part of a follow up in these studies is looking at pregnancies that may occur. After this study. We're very we know we have number of those patients who are specifically getting on the trial. So they they can move on to have a successful pregnancies and of course, we look forward to bringing that that great result forward in the future if we can.

Yeah, and just a reminder to the audience here that in the <unk> [noise] preclinical work there has been zero evidence of that if there's any germ line involvement in in any way.

Well the other one other point there is important they talked about before.

Free caller Cry and gene is not needed at all for for a normal life span, so that or or a development or fetal development. So we know very well from humans that 15 is not essential for embryos.

Embryonic development.

Got it they're helpful. Thank you.

The next question comes from Dagon, Paul with Stifel. Please go ahead.

Hey, good morning, guys. Thanks for taking my question just staying with this preclinical idea I guess one of your peers in the Boston area also provided a pretty substantial data from animals I believe it was an H PS as well as mice looking at pretty robust set of data demonstrating the germline, but still got a clinical.

[noise] hold so any additional color you can provide in terms of the size and breadth of this experiment that you think will be sufficient has the F. D. A clearly outline exactly how many sample size that you. They wanna see before they kind of confirm that it is substantial or kind of related to that have they expressed any N from.

The phase two that might substantially get their questions answered. Thanks, so much.

Yeah, I I I would draw a distinction between what I've seen reported in terms of breeding studies and litters et cetera that is not what this is that question has been addressed with information that was supplied with the already cleared I N D. So as far as we can tell.

Oh in her dealings with the F D. A and every other regulatory agency that particular Germline question has been put to rest.

With the data we supplied <unk>. This particular study asks a different question which is.

Does the embryological development of Ah Ah Ah Ah a fetus in mice be affected potentially in any way by having been exposed to call. It the chemicals, even that are part of an LNP. This is something that is typically done with many agents.

<unk> the distinction in this case is that this is being done a little earlier than would typically be the case, which as we said at the outset I think it's just F. D. I take it you're very considered view, we do have agreement with the study it's as I said, a modified or I'm, sorry, it abbreviated Ah study, which is.

Quite readily addressed and something that we're well on our way to completing so it's standard stuff and we look forward to sharing that information with the F. B I.

Great. Thanks, so much sure.

The next question comes from miles Minter with William Blair. Please go ahead.

Hi, Thanks for taking my question just another one on preclinical studies. Thanks for <unk> started all of your programs just using a different died does this particular practice I didn't need to be generated per product are deeply just once for the plot for it.

My message sort of cover uhm cycle stomach.

Well, well I can't speak for what the F. D. A will ultimately require it is generally applicable as you point out it's the the LNP itself that determines where the material goes we've characterized as extensively as we said we've done the breeding studies.

And we would expect the results to be no different with any other guide. So I do think in many respects this should be a platform answer whether or not the F. D. A will immediately see it that way remains to be seen but I I <unk>. That's how we think about it and and they may ultimately as well.

The next question comes from Brian Cheng with J P. Morgan please.

Please go ahead.

Hi, This is sung in I'm from I'm I'm working with Brian Chang. Thank you. Thank you for taking our questions. What's the latest one at a T. T. R. Poly neuropathy and when do you think you'll be able to give you a bit more granularity on the timeline for a piano study in pine Uropathy and what are some of the Canning factory.

If any thank you.

If if you want to address that yeah, what what we've we've been saying and have said is that we are we are preparing the design of the pivotal studies.

This is obviously, we now have a lot of information from patients followed more than two years will be.

Talking more about that data later this year.

And so that that that's where it is at this point, we're not guiding exactly two in that trial will start yet the.

In terms of.

<unk> Oh, the gating factors. Yeah. This is what will be great going into this next study of course has all the C. M. C issues will all be resolved you know a lot about safety in both patients would probably neuropathy in cardiomyopathy. So there there are very few gating factors other than getting regulatory agreement on the trial design and that's the prime.

Everything we're looking for is the regulatory feedback at this <unk>.

Thank you.

The next question comes from William Pickering with Bernstein. Please go ahead.

Hi, Good morning. Thank you further question as.

Do you think about the the C N trial design and the time that it will take to show and outcomes benefit alright are there other in points that you might be able to.

Update investors on as the trial progressive and use these to point towards the differentiated clinical profile, even before we see the outcomes data.

And very quickly could you share what sorts of clinical endpoints you were thinking of sharing.

Towards the end of this year. Thank you.

David what what could we shared a blinded pivotal trial [laughter]. Yeah. Unfortunately, I think as you you probably recognize your cat sure anything from a blinded trial, because we we don't say anything about the data by arm. So we'll have patients who are on the drug in patients who are off the drug. However, we should say, we we we expect to.

Other studies that will go out the value.

Of the deep reductions in P. P R.

Generally call. These mechanistic studies or that type of study and we won't bring that date of forward as soon as we can you do recognize you know from the phase three that are going on these results do take awhile to mature. They you know this is the the changes don't happen very quickly, but as your screen and everything we've.

We bring forward data when we have meaningful interpretable inconsistent results that we can show you. What the story is so we we will we will wait for that as we whenever we bring up your data.

The next question comes from brick been Koski with cancer Fitzgerald. Please.

Please go ahead.

Hi, good morning Ah Congrats on the progress and just a quick question for me last quarter. It was noted that every dosing of patients from a low dose polyneuropathy arm of 20 or one has started.

I'm curious if we could expect to see any of these data from reducing cohort and the end of your update and what type of data could potentially be shared from these patients.

David do you want to comment on.

Yeah, I mean, what we go all three patients had been dose at this point, it's got it's gone well.

We haven't I don't think we've decided whether to put that into the next update or future update, but we will will will talk about it as soon as we can.

Got it thank you.

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

[noise], Oh, hey, congrats on all the progress and thanks for taking my question can you talk about the rationale and the strategy behind pursuing a C. T. A for 3001 this year, but not an I M D and what are the gating factors in timeline to filing an int. Thank you.

If if you want to speak to her.

Yeah as as we've done in the past I think what you've seen as we look at several things and the first country that we go to look at the the fights that are available the investigative side effects, that's very key to us getting high quality sites. We we look at the regulatory environment, you're all those are pieces of what of what we put together.

And in this case, we did decide as we have in February the other compounds that that going with a C. T. A is the best choice.

Gating factors for an int are are you know similar to what we've had for other Ind's of course, you need the.

The the pieces of C. M C picture as a as a big piece of our applications and and of course getting agreement on on trial design. So all of those things we.

We we are are possible for later submission to these as an I N D.

Great. Thank you very much.

The next question comes from Sylvan <unk> with J P security J M. P Securities. Please go ahead.

Hi, good morning, and thanks for taking my question Uhm I just have a more general question with the Christmas XFL potential approval coming up in the U S. By the end of the year and then potential consequences reimbursement is there anything combos model that we can learn that will be applicable to.

For example, you're achy all programs or is that too far off at this point.

Well, obviously, we watch those spaces very very carefully.

I don't think that the world has converged on a final model for you know drugs like this that are potentially curative, but.

I I.

I see emerging trends and there's gonna be some really interesting I think Ah examples that of course, we will study very very carefully our view right now is to have the best possible drug that moves the efficacy bar substantially forward and captures savings for the health care cyst.

Some et cetera, and I think that that'll be the basis for whatever pricing model, we ultimately come up with but we're confident that the the.

The health advantages in the efficacy that we expect to deliver will be of value to payers and whether it's in the U S are actually less.

Okay.

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

Hi, Good morning. This is Nick out for Steve a couple of questions on a T D.

So are both knock and knock out products intended to target patients with the homeless I guess the genotype.

David you Wanna I per cent.

Yeah that that's really where the need is for the patients who are homozygous. The in terms of knockout. This is patients were the predominant issue with liver disease. That's that's the main thing that the knock out addresses it doesn't address the lung disease and there are a substantial group maybe.

Well I guess, it's it's certainly 15 per cent overall, the patients who who tend to have liver disease and that concludes patient some patients with lung disease.

Big majority of patients of the patients who need the deficiency is affecting the lungs.

And that that is what the knock in it's it's gonna help with like putting into wild type Jean.

Many patients will end up getting both because as they start to live longer the liver disease may become more important the liver disease can be subtle and some patients and a lot of the physicians feel that they would want to give their patients both agents over time and in both these agents to be given should say in either order one can be given before the.

Either either either one could be given before the other so that we have a lot of flexibility in how we treat patients it might be important for small listens to remember that these are independent programs that can be brought together, but we're pursuing them as independent yeah. These are two separate drugs that are gonna be fully day.

<unk> with all all the requirements that you have for each drug that's not.

It's not a combination program per se.

Okay got it. Thank you and then so from your particular preclinical work do you expect the same level of beautiful last ace inhibition with the a T protein induced by 3001 compared to wild type M. A T protein.

What we've presented in nonhuman primate word.

Is this approach was able to reproduce levels seen in non-human primates that were essentially indistinguishable from normal human levels of circulating alpha one so.

Yeah.

Target is to accomplish just that in patients and you know the preclinical models suggest that we may will be able to do that.

Laura.

I had to how we're thinking about out for them.

Yeah, and it looks like you need to ensure that that's only had pregnant leathers those inappropriate <unk>.

<unk> D V D E like you need to have.

John I'm trying to describe that's what we accomplish and that <unk> and that that the expectation that's going to translate the humans.

Got it thank you for the next.

The next question comes from <unk> with Goldman Sachs.

Please go ahead.

Hi. This is your natural emphasizing thank you for taking my question.

So a couple of questions the first time.

2002 in your data.

You mentioned that patients now to reach all from a militant axis and they've not experienced subsequent attacks any further updates on these patients.

<unk> remained a taxi to date.

And on your toes using a one program could you provide some colonial life.

Discussions with the F D a.

C M M. P N have spoken about what they would like to see in the pivotal study. Thank you.

Maybe you could remind.

That's the day that we presented on 20 O. Two and then I'm sure we'll be having updates as time goes on but yeah. So I think you recall, we did give updated data fairly recently on 20 O. Two recall with all the patients who have received prophylaxis, we're able to withdraw it and none of those patients that had a subsequent.

Tak in that report I should mention that.

We didn't use Latin Italian math is one of the withdrawals because it would affect our biomarker measures. However, what we're seeing in the phase two as we did allow tell your mouth withdrawal and that is we have a number of patients will be treated after that withdrawal.

So stay tuned more data is coming for that as well.

When we talked to regulators about the phase III you know the I M D as in.

Had preliminary discussions but of course to get agreement that involves the I M. D submission that we're doing.

In September for the F. D. A also had extensive discussions with with regulators outside the U S. We feel very good that our trial design will address the question that that that that they will have.

For P. M. We are a little earlier you know we did we did push it first on C. M. As a much larger medical need more patients needing this but also with P. N and she said you know we will bring you forward more details as we get agreement or the pivotal trials is on.

The next question comes from Richard Long with Credit Suisse.

Please go ahead.

Hi, Good morning can you discuss the market opportunity for H E E outside the U S based on the reimbursement it'd be such wasteful brand products so far.

And what did the learning for 2002 I should think about issue that's market that you would need to include me in your study.

The bulk of the H E market today resides inside the United States, we're well aware of that we do have an eye to what we can deliver outside the United States. What we've seen during the course of our phase one and now face too.

Work is that there's a great desire to have these products.

And we will do our very best to show that not only does the product.

Worked very very well, but that it can be resource sharing to those typically centralized systems.

So to the extent that that market opportunity exists we want to participate in it to the greatest extent possible.

Can you compare and contrast, the reimbursement for U S versus six U S. Just curious to see how.

Markets would affect the product.

I think that's something we can address later on as we get further down the road, but generally speaking.

You know this this information as well publicized and available the market has been disproportionately U S markets with reimbursement rates that are higher that's typically the case for most drugs and again, we see that here, but again.

We're trying to think through how this particular approach can be demonstrated b resource sparing too what are typically centrally reimbursed approaches and will present that data to those you know different systems and we expect it will be of a potential value to them.

Great. Thanks.

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

Great. Thanks for all the terrific questions and for your continued interest in and tell you in our progress and we look forward to future updates so have a great day and have a great rest of the week.

The conference has sent it you may now disconnect. Your line. Thank you.

[music].

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