Q3 2023 Intellia Therapeutics Inc Earnings Call
Speaker 1: Good morning and welcome to the Inteliaphera Putics 3rd quarter 2023 financial results 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.
Good morning, and welcome to the Intel Biotherapeutics third quarter 'twenty Q3 financial results 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.
Corded 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.
Speaker 1: As a reminder, all participants are currently in listen only mode.
Speaker 1: If anyone requires operator assistance during the conference, please press star zero on your telephone keypad.
Speaker 1: I will now turn the conference over to Ian Carp, Senior Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.
I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and corporate communications at <unk>. Please proceed.
Speaker 2: Thank you, operator, and good morning, everyone. Welcome to Intelliath Air Pudding's third quarter, 2023, Erning.
Thank you operator, and good morning, everyone welcome to <unk> Therapeutics third quarter 2023 earnings call.
Speaker 2: Earlier this morning, Nteli issued a press release outlining the company's progress disorder, as well as topics for discussion on today's.
Earlier. This morning until you issued a press release outlining the Companys progress this quarter as well as topics for discussion on today's call.
This release can be found on the investors and media section of <unk> website at Telia, TX Dot Com. This call is being broadcast live and a replay will be archived on the company's website.
Speaker 2: called being broadcast live and a replay will be archived on the company.
At this time I would like to take a minute to remind listeners that during this call and Telia 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.
Speaker 2: All information presented on this call is current as of today. And then tell you undertakes no duty to update this information unless it requires.
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.
Speaker 2: Joining me from in tell you are John Leonard, Chief Executive Officer, David Lebelal, Chief Medical Officer, Laura Steploransino, Chief Scientific Officer, and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights, David will provide
Joining me from Italia are John Leonard Chief Executive Officer, David Lebel, Chief Medical Officer, Laura step Lorenzini, Chief Scientific Officer, and Glenn Goddard Chief Financial Officer John.
John will begin with an overview of recent business highlights David will provide an update on our clinical pipeline progress.
Speaker 2: Laura will review our R&D updates and Glenn will review our financials before we open up the call for questions. At which time, Eliana Clark, our chief technical officer will also be available. With that, I'll now turn the call over to John , our chief executive officer.
Laura will review, our R&D updates and Glenn will review our financials before we open up the call for questions at which time Eliana Clark, our Chief Technical Officer will also be available.
With that I'll now turn the call over to John <unk>, Our Chief Executive Officer.
Thank you Ian and thank you all for joining us today.
Speaker 3: At Intelio we're at the forefront of realizing the promise of genome editing and unprecedented
But I'm, telling you we're at the forefront to realizing the promise of genome editing in unprecedented ways because.
Speaker 3: Through the remarkable efforts of our experienced team, we recently received FDA clearance to begin the first-ever pivotal phase III trial of an Invival CRISPR B-
So is the remarkable efforts of our experienced team. We recently received FDA clearance to begin the first ever pivotal phase III trial of an in vivo CRISPR based therapy.
Speaker 3: This marks until the second in Vivo I&D that the agency has cleared this
This marks intelius second in vivo I N D that the agency has cleared this year further demonstrating our deliberate and systematic approach to drug development.
Speaker 3: Further demonstrating are deliberate and systematic approach to drug development.
As a result of our commitment to high technical standards, whether in basic research assessing safety manufacturing or in the clinical development of our drug candidates. We've moved another step closer towards ushering in a new era of medicine.
Speaker 3: As a result of our commitment to high technical standards, whether in basic research, assessing safety, manufacturing, or in the clinical development of our drug candidates, we've moved another step closer towards ushering in a new era of medicine.
With the imminent start of the phase III French late 'twenty, one and Kelly is now a late stage drug development company.
Speaker 3: With the imminent start of the Phase 3 Fren 2-8-20-01, Intelios now a late stage drug development.
Speaker 3: As David will go through a more detail, the latest in-rambata give us confidence that M.P.O.A. 2001 could potentially reset the standard of care for ATTR M.L.A. dose.
David will go through in more detail the latest interim data give us confidence that until late 'twenty one.
Potentially reset the standard of care for ATT amyloidosis.
Speaker 3: These data, now from over 60 patients, showed a favorable safety profile, as well as consistently deep and durable TTR reductions following a single end.
These data now from over 60 patients showed a favorable safety profile as well as consistently deep and durable T. T. R reductions following the single infusion.
Speaker 3: Alongside all the progress we've made with NKLA 2001, our broader pipeline and platform continue to advance as well.
Alongside all the progress we've made with <unk> 21, a broader pipeline and platform continue to advance as well.
Speaker 3: We're only weeks away from the planned completion of patient enrollment of the NTLA-2002 Phase 2 study for HAE. This means we are now approaching 100 patients dosed with either of our two lead in vivo candidates.
We are only weeks away from the planned completion of patient enrollment of the until late 'twenty two phase two study great Jay eat.
This means we are now approaching 100 patients dosed with either of our two lead in vivo candidates. Additionally.
Speaker 3: Additionally, we expect to submit a regulatory filing to begin clinical development of our first wholly owned in vivo gene insertion program, N-T-L-A-30-01, and Q-1 of next year.
Additionally, we expect to submit a regulatory filing to begin clinical development of our first wholly owned in vivo gene insertion program until a 31 in Q1 of next year.
Speaker 3: Overall, 2023 has already been a highly productive year, and there's still much more to come in the week.
Overall 2023 has already been a highly productive year and there's still much more to come in the weeks and months ahead.
In this challenging financial market that has impacted our entire sector. We continue to further tighten our financial management to turn the promise of gene editing into reality for patients our balance sheet remains strong and we are prioritize some programs and platform innovations, we believe will address unmet need.
Speaker 3: In this challenging financial market that has impacted our entire sector, we continue to further tighten our financial management to turn the promise of gene editing into reality for patients.
Speaker 3: Our balance sheet remains strong and we are prioritizing programs and platform innovations we believe will address unmet needs and provide the greatest value to our shareholders.
Needs and provide the greatest value to our shareholders.
Speaker 3: We're acutely focused on the efficient and rapid advancement of our two lead in vivo programs, and their anticipated future commercialization.
We are acutely focused on the efficient and rapid advancement of our two lead in vivo programs.
Our anticipated future commercialization.
Speaker 3: I'll now hand the call over to our Chief Medical Officer, David Leblow, who will provide an update on our clinical programs. David?
I'll now hand, the call over to our Chief Medical Officer, David Loeb Wall, who will provide an update on our clinical programs David.
Thanks, John and welcome everyone.
Speaker 4: I'll begin with 2001, our In-Vivo CRISPR-based candidate for the treatment of ATTR Amoidos.
Begin with 20th one our in vivo CRISPR based candidate for the treatment of H T. T. R amyloidosis.
Speaker 4: We were pleased to present updated interim data from the Phase I study at the fourth international APTR AMOLEDOSIS meeting for patients and doctors last week.
We were pleased to present updated interim data from the phase one study at the fourth International H T. T. R amyloidosis meeting for patients and doctors last week.
Speaker 4: The data presented from the largest in vivo gene editing study run to date were from the initial 65 out of 72 patients.
The data presented from the largest in vivo gene editing study run to date were from the initial 65 at a 72 patients.
Speaker 4: The results from the final seven patients dosed or enrolled after the data cutoff will be reported at a future date.
The results from the final seven patients dosed were enrolled after the data cut off will be reported at a future date.
Starting with safety, 20th one was generally well tolerated across all patients at all dose levels tested.
Speaker 4: Starting with safety, 2001 was generally well tolerated across all patients and at all dose levels tests.
Speaker 4: The most commonly reported adverse events were infusion-related reactions.
The most commonly reported adverse events were infusion related reactions.
The majority of adverse events, including infusion related reactions were grade one or two in severity were transient and resolved spontaneously.
All patients received a full dose of 20th one and remain on study.
In summary, the 20th one safety data continues to be encouraging.
Moving onto the activity data that begins on this slide.
In the newly reported dose expansion portion a single dose of 20th won at the 55 milligram and the 80 milligram dose that's a profound reductions in serum T T our levels.
These results were consistent with the data previously reported from patients in the dose escalation portion who received the corresponding weight based dose of 0.7 milligrams per kilogram and 1.0 milligrams per kilograms, respectively.
Across all 62 patients who received a dose of 0.3 milligrams per kilogram or higher the mean and median theorem Q T R reductions with 90% and 91% respectively at day 28.
The three initial patients who received the lowest dose of 0.1 milligram per kilogram have all received a follow on dose of 55 milligrams and these data will be presented in the future.
On the next slide you'll see for the first time, the absolute residual E. P. Our concentration levels for all 62 patients dosed with 20 O one.
These data are striking in comparison to what you would expect to see with RNA silencing.
Regardless of the patient's baseline P T. Our level all patients reached a low level of residual teach yard concentration and then as expected with our gene editing modality stayed at these low levels.
With over 20 patients now having meets at least 12 months of follow up these patients continue to show long lasting response with no evidence of loss in activity over time.
As Dr. Gilmore highlighted in his talk last week or the clearance of amyloid is invariably slow and occurs at different rates and different organs.
Concentration of amyloid protein matters.
As seen with other types of amyloidosis, achieving a greater reduction in circulating concentration of the amyloid precursor protein.
Associated with a better clinical outcome.
And here with a T T R amyloidosis, we anticipate seeing similar results.
The persistently low levels of T. T. Our concentration achieved with 20 O. One are expected to reduce the rate of ongoing amyloid formation and hold the possibility for amyloid clearance to reverse the symptoms of the disease.
We have also observed early signs of clinical activity in the initial cohorts and look forward to presenting the first clinical data beyond GTR levels. Once we have longer follow up across all cohorts.
We believe these encouraging interim data bode well for what we'll see in the future.
These data also support the selection of 55 milligrams as a dose for further evaluation in the phase III trial.
Now I will share for the first time more information about the pivotal trial design.
The 20th one magnitude trial is a global randomized double blind placebo controlled study.
It will enroll approximately 765 patients.
Living with H T T R amyloidosis, with cardiomyopathy, who have either the hereditary or wild type form of the disease.
The study is designed to enroll patients on concomitant to families and patients who are the families naive at baseline.
Patients will be randomized two to one to 20 O one or placebo.
Patients randomized to the active drug arm received a single 55 milligram infusion of 20 O. One.
The primary endpoint is a composite endpoint of cardiovascular related mortality.
And cardiovascular related events, such as urgent heart failure visits and hospitalizations.
The study will read out when both a pre specified number of events have occurred.
And the final patient has completed at least 18 months of follow up.
Secondary endpoints include serum T T our levels and the Kansas City Cardiomyopathy questionnaire score.
Notably if needed we will be able to adjust the trial. The protocol amendment based on the learnings from others in the space and the protocol includes an optional interim analysis, which could provide an earlier readout.
Moving to the next slide we are poised for rapid initiation and enrollment in the phase III study.
To start as quickly as possible we began preparations for this pivotal trial months ago.
We have selected the majority of our clinical sites around the world and has seen great enthusiasm from investigators.
Additionally, patients themselves have expressed strong interest in enrolling in the program, including here in the United States.
If enrollment goes as quickly as we hope it does we are well prepared to supply the drug product needed.
The majority of 20th one for use in the study has already been manufactured employing the same process and facilities to be used in the commercial setting.
As previously guided we are on track to initiate the study by year end with patient dosing to commence early next year.
I'll now turn to 20 O to our in vivo CRISPR candidate for the treatment of hereditary angioedema.
In October the EMA granted prime designation to 20 O two.
Just on the positive interim data from the phase one portion of the ongoing phase one two study.
We're very pleased to received prime designation because it is only awarded to drug candidates that may offer a major therapeutic advantage over existing treatments.
With Prime we gained valuable regulatory benefits with a goal of getting 20 O two to patients as quickly as possible.
As John mentioned, we are on track to complete enrollment of the phase II portion by year end.
We're also on track to complete in the first half of next year. The additional mouse study requested by the FDA and expect to initiate the phase III as early as third quarter of next year.
One of the key advantages of our modulus platform is our ability to apply the learnings from one program to another.
We will certainly be incorporating the learnings from the success of our recent 20th one regulatory process as we prepare for the 20th two phase III.
The strong momentum continues for intaglio with two active phase III studies for our lead in vivo program expected in 2024.
I'll now hand out there to lower our Chief Scientific officer, who will provide updates on our R&D efforts.
Thank you David Good morning, everyone. We're entering the next stage of innovation, our everything under any rate solutions.
In vivo setting we have three near term priorities. This includes clinically validating our gene mutation platform moving our gene editing capabilities outside the liver and continuing to expand our comprehension Jean anything toolbox.
Starting with in vivo gene expression with trying to submit its CPA for NPL a good one in Q1 of next year.
First of all we believe India later in Q1 will be a major advancement for people, leaving with a nine month gestation of Alpha one antitrypsin deficiency.
In parallel our cause.
Elaborate a heck of a turnaround plan to initiate the clinical staffing mix here, where I wasn't trying to develop the factor nine gene insertion programs, especially machine yet.
Next building on our CRISPR against nine anything expertise, we're making strong progress with additional 18 months.
As we announced today, we will be hoping further A&D amazing activities for NDA late 'twenty three.
In vivo candidate for the treatment of it 10% to 15%.
One patients with liver disease to prioritize it research program for Alpha one utilizing our DNA ranking technology.
Finally, we started to see a new collaboration to accelerate gene editing capabilities outside the liver.
In October Italian, Virginia announced an expanded research collaboration to jointly develop in vivo programs for the treatment of neurological and muscular diseases.
This collaboration Leverages, our proprietary and they need to Chris Perkins nine systems in the generalist antibodies kind of get there.
Victor delivery technology.
We're excited to deploy any need to cause nine it comes back to Chris for enzyme well suited for E. V E rate in combination with a genome technology can potentially solve delivery to other tissues outside the liver.
Regeneron has also exercised its option to extend the existing technology collaboration time, we didn't tell you for an additional two years until April 2026.
Alongside our work with Virginia earlier, this quarter Sperry, Michigan analysis election, Okay, compared again, that's part of our collaboration to develop novel genomic medicines for the treatment of ocular diseases.
Looking ahead in addition to advancing our own in vivo and ex vivo programs. We will continue to seek partners to maximize the value and impact of our proprietary technology.
I'll now hand over the call to Glenn our Chief Financial Officer, who will provide an update on our financial results and third.
Third quarter 'twenty 'twenty thing.
Thank you Laura and good morning, everyone and tell you continues to maintain a strong balance sheet that allows us to execute on our plans to advance our pipeline and platform.
As shown on this slide our cash cash equivalents in marketable securities.
Approximately $993 million as of September 32023.
Compared to $1 $3 billion as of December 31st 2022.
Please note. This does not include the $30 million Tech collaboration extension payment from Regeneron expected in the first half of 'twenty 'twenty four.
As we move forward in the current capital market environment.
We will continue to be selective with how we deploy capital and we'll continue to make important portfolio prioritization decisions to support our continued growth.
One such example is the decision to halt further IND, enabling activities for <unk> 'twenty L. Three as Laura mentioned earlier prioritize our research program using our DNA, writing technology for Alpha one.
Looking ahead, we do not expect a significant uptick in our operating expenses as we get closer to having two phase threes up and running it would tell you.
We have built a modular LNP based platform, where our manufacturing processes and drug components are largely the same across multiple programs.
Unlike viral based gene therapies are drug components of synthetic with well established manufacturing rightly available. Therefore, the cost to manufacture it's significantly less expensive than traditional gene therapy.
In addition for NPL a 'twenty one we have finished scaling up our manufacturing process to meet the needs of the pivotal trial for which a majority of the drug product has already been manufactured.
We anticipate being able to leverage the same process in the commercial setting.
As a reminder, regeneron covers 25% of the Entel a 'twenty one costs.
Finally for entail a 20 O. Two we anticipate the phase three study to be small relatively quick to enroll and complete.
In summary, we continue to efficiently deploy our resources with a heavy emphasis on advancing our two lead programs towards commercialization.
Expect our cash balance to fund our operating plans beyond the next 24 months and with that I'll turn the call back over to John for closing remarks.
Thanks, Glenn I.
I want to close by acknowledging that while it's been an exciting year filled with many milestone achievements for until.
We're already focused on what lies ahead.
We're only weeks away from the anticipated start up of our phase III study for until late 'twenty one.
To begin the phase III for until late 'twenty or two next year.
With the start of these two pivotal studies, we will move one step closer to commercialization and ultimately profitability what was once a distant hope to turn Christopher to medicines is now quickly within our grasp.
Finally, I'd like to take a moment to thank the incredible team at <unk> as well, so physicians and patients involved in our clinical trials. That's the true trailblazers in this field without their passion dedication and courage, we would not be entering this next phase of innovation towards the new era genomic medicine.
With that well now open the call for your questions. Operator, you May now open the call for Q&A.
Hmm.
We will now begin the question and answer session to ask a question you May Press Star then one on your Touchtone phone.
If you are using a speaker phone please pick up your handset before pressing the keys to withdraw your question. Please press Star then two.
Please limit yourself to one question.
At this time, we will pause momentarily to assemble our roster.
The first question comes from Costa is Flores with BMO capital markets. Please go ahead.
Hello, Good morning, everyone and thanks for taking our question maybe one question I will just stick to one question.
Can you discuss a little bit about that.
Whether the tire Lisa is powered to demonstrate statistical significance of our 2001 on top of the families in each case and what percent that just tough on me. These.
Baseline, you're allowing Italian thank you.
Hmm.
Well I'll ask David to address that.
Part of the question was how much do we think it will be in the trial and how repowering it versus actually sounds fabulous. Thank you Catherine.
Hmm.
Tonnage of patients, we estimate will be about half the patients will be onto family as you know to families who is becoming a standard care in many places around the world. So there will be extensive use them.
In terms of powering the study has a 765 patients is powered to show an improvement of the active arm versus the placebo arm, including patients who have either to families or notes are fabulous.
Benefit in patients with their families.
It can be discerned by looking at the sub subgroup analyses, which will be because patients are stratified by the use of your covenants.
The next question comes from Joon Lee with Truest. Please go ahead.
And congrats on the progress.
Buses.
You can say that in two parts of what it means to be Frank there, but we definitely see T O.
Any incremental debt.
Sufficient to differentiate versus one why drill clinically.
Yes.
June I'm, sorry, I'm going to have to ask you to say it again.
The call is very very garbled.
Just give it another.
And another shot.
Yes sure.
Do you think the incremental gas and adoption will be sufficient to differentiate for us since we are in the ICU.
Yeah.
Okay.
Yes. This is David.
Yes.
Reduction that we're seeing and you've seen here.
Median of 90%.
Is really having the amount of the P. T are thinking about it as absolute levels that you see with violence. There was a fire in somebody's got about an 80% reduction.
What we've shown in this recent presentation.
Is absolute levels of about 72 microgram.
And the.
So of course, I have about double that but 80% reduction.
If you look at Oh, No Islands data for example, empowering neuropathy you do see that there's actually a greater than proportional benefit as you reduce.
The GTR protein so.
So we do think this will make a significant clinical benefit for patients.
And that's what we would plan to proof in our phase III trial.
Thank you.
The next question comes from money real.
Zero harm with Leerink partners. Please go ahead.
Hey, guys. Thank you very much for taking the question.
A couple of quick follow ups regarding that approximately half the fabulous number.
I presume that is not the pop the proportion of the patients do you expect to be at its fabulous.
Match spaces at baseline or is that your estimate or is that your estimate of the proportion of patients that will be there.
It will be at the candidates across the course of the study, including drop it and I have one more follow up.
Do you want to address that David Yeah, I was referring to the number of patients at baseline we have anticipated that during the study some patients may start onto families. After that and obviously, we'll be monitoring this during the trial.
Great and obviously you guys have taken a slightly different approach around event around sort of flexibility around reaching an event rate on its put on on time horizon as opposed to setting a very prescriptive 30 month endpoint for example, how should we think about.
What is the target product profile you guys are looking for it.
In terms of.
Are you targeting a relative risk ratio on your label that looks like the original Cabot. A study are you thinking in terms of absolute reduction in terms of number of mortality. How do you think about the target product profile. They are trying to generate from this study presuming you continue to see a robust benefit knocked out that you've seen thus far.
Yes.
Yes.
Stand the analysis of the more recent studies not as you say the attract study used a different statistical methodology, but the recent studies are looking at reduction in risk of both a composite.
Cardiovascular events and cardiovascular mortality for us. The other studies are suddenly different from people look at total mortality and other small differences, but overall.
Uh huh.
Current studies and there arent growing are using are fairly similar.
Point, and and look we'll be looking at the benefit in a similar way.
Great. That's helpful. Thanks, guys.
The next question comes from Ryan for Seth with Guggenheim. Please go ahead.
Hi, everyone. This is ray from Deb <unk> team, so for enrollment objectives and the magnitude study what is the importance or target for inclusion of the N Y H a class three subjects.
David.
Right Yeah.
Yeah, Yeah, we have not set a target for that we will be monitoring the number of class III patients in our study I think what you'll see is we are looking for patients who are at risk.
We think that if you have two healthy patients of course, the drug doesn't make much difference because there arent any events either with or without an active drug.
But in terms of class III patients. We do think we have the potential to benefit them with our deep reductions in Q T. R. A consistent reduction in C. T R and we'll be looking at that in the clinical trial.
Thank you.
The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Great. Good morning, guys. Thanks for taking the question I'll, just pivot a little bit to the latest presentation at ATT amyloidosis meeting I wanted to get a clarification on the safety data specifically on the cardiac failure tabulation on slide 10 of the presentation you saw grade two and grade threes can you clarify.
When or what kind of events. These were thanks so much.
Yeah, Chris these are patients in the trial will have.
Heart congestive heart failure and these are patients of course, who are at risk of having exacerbation of that in the course of their disease.
So these are patients who in the course of their disease did have a worsening and that's really what we can say about them. It's just that as you can see it's a very small number of patients among a group of Ah now a total of 75 patients or more than half of which are about half of which are patients with cardiomyopathy.
Great. Thanks, so much.
The next question comes from Maury Raycroft with Jefferies. Please go ahead.
Hi, good morning, and thanks for taking my question.
The size of the pivotal is larger than than our Helios b, but it seems like the duration of the study has options in it where it could be stopped early can you talk about the proportion of patients you will need at 30 months and the pre specified number of events needed and what are your expectations for enrollment timelines and when an optional interim could occur.
Okay.
It's hard to get all of that so we are not setting.
On a particular number of patients would be at 30 months, but large proportion will be at 30 months, even with an event driven trial. However, the advantage of advantages of our event driven trial is that when you will be following patients beyond the 30 month point for your patients who are going longer you get more information from them and there will be some patients who have less than 30 months.
We're not yet giving guidance on completion of enrollment.
And we're not talking in detail about the number of events at this point.
Okay is there anything more you can say about the optional interim and what would be factored into that.
Yes, I think the interim analysis will be obviously looking at data from other studies to understand the benefit of reducing T. T. R. With violence, There's for example, and understanding.
Hum.
And be able to decide whether to keep the interim analysis or not depending on how our historical data is growing with other studies.
Got it okay. Thanks for taking my question.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you for taking my questions I also have a few regarding our phase III study design for kitchen electrics yourself on it.
So just from a philosophical point of view of all the other studies, we see no I, 50% close to 50% of our baseline path is because actually it was earlier study and took a few years. So now the dynamic of change just wondering why.
Right now our country or do you think about just 100.
100% every patient will have and that will have a definitive results, whether you will be shipping already against the caf mono therapy, and also will help with the stats.
And the second question is also regarding the stats methodology.
It is a method that we use for the phase III study.
That flexibility when you cannot modify.
Well be planning to expanding our ball patient numbers or.
Planning to wait two more events.
Reach.
Yes.
With the last one yes, we are there is flexibility to modify the design before it's unblinded. So again, we will be watching the results from other trials as we decide the best way to do that.
I think it's less likely that we'd want to expand the number of patients and to follow them for a longer period of time I think as you've seen in the other studies that benefit tends to come later in the trials after about a year of treatment in those trials were hoping that will come earlier in our trial, but still it does seem to be some delay in the benefit.
Reducing.
The amyloid.
We're not talking about the exact methodology, but as I said it is similar to what the other studies are using.
And we don't think it's you know there are a lot of countries that still do not have the families. We think that looking at the benefit in patients don't have to families will be an important finding in the trial as well.
The next question comes from.
Solving Richter with Goldman Sachs. Please go ahead.
Good morning, Thanks for taking my question.
Okay, the 18th and cool program 2000, and greed and.
Can you just walk us through what you saw pre clinically to just continue this program and just your thoughts about why.
<unk> technology can move forward with here. Thank you.
I'll take that Sean.
We looked at.
The.
Strict liver manifestations of Alpha one antitrypsin deficiency, which is what plenty of three would address.
We see that as well.
What is <unk>.
Pretty small subset of all patients estimated 10%.
15% actually experienced that and so as we balance that opportunity versus the progress, we're making with the Chi writing approach, we thought that the better deployment of our resources was to the cheap writing, which.
Again, just making good progress.
And in the preclinical setting.
We will have more opportunity to talk about that as time goes on but one of the things that we're very excited about it.
Just deploying that technology, even more broadly in other conditions.
The next question comes from Luca <unk> with RBC. Please go ahead.
Oh, great. Thanks, so much for taking my question, David apologies for coming back to you I guess.
Could you just talk about 221 randomization here is that something you proactively pitch USDA or ask you to do with just one randomization trial. So you can collect more safety data from the active arm given the novelty of this technology any thoughts there would be much appreciated and then maybe if I may.
Can you just talk you already alluded to <unk> can you talk about why cardiovascular mortality and not all cause mortality. Thanks, so much.
Okay. Yeah in terms of the two to one randomization that this is our decision. It was agreed by regulators around the world.
Hey, it's favorable for patients of course entering a trial.
So that's there's a lot of that these patients will.
No likely the placebo if the trial is positive we will likely allow them to go on for active drug or would you have to make attractive drug available to them at that point, but it really is in the interest of the patients. We do get as you say more safety data as we possibly could get by crossing patients over to active drug.
The.
The CV mortality, we think is the more important endpoint here it wont be you know.
All cause mortality can have noise from other causes of mortality in this elderly population. So we do want this really to be looking sharply.
That we have on cardiovascular events and.
Mortality.
Got it thanks, so much.
The next question comes from John <unk>, Xu with Wells Fargo Securities. Please go ahead.
Great. Thanks for taking our questions just following up on the two to one ratio.
If the trial size is similar as the Helios B.
But the randomization is two to one as opposed to one to one does that imply.
That's your assumed effect size could be greater.
Then RNA silencers and also just wondering.
When might we.
Have an insight or understanding.
The treatment.
Treatment effect versus silence or do you think we have to wait until the conclusion of the phase III study or perhaps there could be early signals from your I think the last study such as.
Evidence from NT Pro BNP Oh other evidence. So if you can comment on that that would be great. Thank you.
Yeah.
So we do think that the effect size would be greater than seen with RNA silences didn't you know you can we felt this was very well powered even if the effect size is similar to the RNA silence or is it is a large trial and it is has very high powered to look at differences in the two arms.
Turning to the second yeah, we do think there will be some insights coming from the phase one study of course it for non randomized study with a relatively small number of patients what we do with shrink with sufficient follow up.
I'll have some some evidence perhaps we might have evidence that this is better than what's happening with Gardner silencers.
Great. Thanks for the color.
The next question comes from Doug Harrison with Bank of America. Please go ahead.
Hey, good morning, and thanks for taking the question.
For the absolute residuals, there TCR concentration you've talked about.
Can you help us understand your view on what level is clinically meaningful and where you could potentially see disease rehearsal.
Yeah.
So we think as we've seen in other studies, reducing GTR, it's important to see any clinical benefit, but what we've also seen as you get greater benefit with lower levels, you get greater benefit, particularly more than proportionally as you get to very low levels. An example outside of Ctr of course is light.
Change disease, where patients with complete response.
Survival that looks close to normal they don't they don't get heart failure.
Significantly.
The the other piece of what we have with our reductions is it's quite consistent you've seen the standard error on our on our levels almost all patients who achieve that low level, which is something that hasn't been achieved well with with RNA viruses.
We can't and we are looking at different ways of understanding reversal of disease, because it hasn't been seen before we will have to look at our own data in order to understand that better as we move forward.
Got it thanks for taking the question.
The next question comes from Joseph Thome with Cowen.
Mr. Tom I'm not sure if it's possible to lower the volume in the background.
Please go ahead.
Sorry about that I'm at the airport, but good morning. Thank you for taking my question, maybe just one on H D. D. Can you just give us an update on where you stand in regards to the H E E.
Hum.
The preclinical data that you need to allow dosing and the women of childbearing age and if that has any implications for the Q1 'twenty four anticipated IND submission for <unk> do you get them back gender a dispersion in the age of onset for their dedication as well. Thank you.
Yeah.
Yeah, so the stub.
So this is gonna be completed well before the phase III starts in the first quarter of next year of 24.
And.
Let's see so it's on track for the first half.
The second question was about Alpha one I think about that.
Yeah, well if completion of that relates to the Q1 filing an ATB at all.
For three years or more.
They're unrelated.
It's not related to that right now.
Thank you.
The next question comes from Lisa <unk> with Evercore ISI. Please go ahead.
Hi, I just have a question about the study can you maybe describe for patients that can start on tap out.
To account for that in the trial it seems to me that.
You know there's there's the rest of it you might have more of that and the people who are not on.
On Tuesday runs are ones. Then so then how do you feel that that's exactly thank you.
Yes. So that is that is possible to patients who are because we think affect the active arm to be doing better there might be a bias towards a patient starting to families in the.
The placebo arm b.
A couple of things, we do ask that the patient would start this after a year of therapy that they not planted.
From the beginning of the study not to plan to start a family.
Until the beginning of the study and the the way you can account for it is to assume that those patients at least after a year because it does take a year for families to have a benefit in terms of events. After that year, there will be some improvement in the placebo arm due to the number of patients crossing took their families.
Okay. Thanks.
The next question comes from Rick been Koski with Cantor Fitzgerald. Please go ahead.
Hey, good morning, Congrats on all the progress I also have a question about the candidates in the Apollo B trial the benefit in the active arm was driven by patients who are not also treated with their families.
Just curious to hear your thoughts on that observation and if you think that effect was specific to the six minute walk test endpoint or that's also something that could potentially emerge from cardiovascular endpoints.
Yeah, I think what we saw in Apollo overall is that they did not follow the patients long enough to understand the potential benefit of reducing T. T. R. So the small differences that we saw in the two arm, it's hard to attribute it.
The weather benefit that combination with the families are not what's important for other on other factors, we do hope that that trial matures they may.
They always get additional results, though of course that may be highly diluted by the fact that they cross patients over.
Cause violence or the placebo patients.
And we think we didn't learn a lot about benefit in that trial, we did learn about event rates and other things from it but unfortunately not about.
The value with the five of them.
Different will be the Helios B trial, which they've said will be coming in the first half of 'twenty four but we should have much more information with longer follow up about combinations with the five minutes or without for families.
Alright, great. Thanks for the color.
The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.
Hi, Thanks for taking the question maybe.
Maybe just one clarification on Tuesday, or zero, one manufacturing it sounds like you're obviously, making product now ahead of the out of the phase III, but just wanted to ensure that there were no other changes planned on manufacturing that.
You needed to make as you scale for potential commercialization.
Marshall product post the phase III, so that everything from this process. That's been used in the phase III is what you're going to use for the commercial product. Thank you.
So we'll turn Giuliana Clarke, our Chief Technical Officer, who can talk about where do we stand with the manufacturing and supply yeah. Good morning, and thank you for the question.
So when we initiated the phase one trial for 2001, we knew who is going to need to adult many patients. So we'd be up for the phase III pivotal trial, and so we began that activities to scale up the manufacturing process and then get to the facilities, what we intend to commercialize so.
As mentioned by both Glenn and David we already manufacture the majority of it that we need in manufacturing it weakened manufacturing processes that we intend to use in the commercial setting and also in the facilities that we intend to use a commercial phase and this is what we include it in that I N D that we filed with SBA.
Yeah, we don't anticipate making any changes.
One you know.
We enter commercialization will stake.
And you can see.
The next question comes from Brian Cheng with J P. Morgan. Please go ahead.
Morning, guys. Thanks for taking my question the empty pro BNP cut off in your phase three is higher than the one seen in Apollo B and that should go see M. Can you comment on a cut off here how might that higher cut off potentially affect the distribution of the N y shaped class and baseline TGI level. Thank you.
Yeah. So we did choose a higher level 1000, and the idea here talking to our experts around the world, including our steering committee is that patients who are very healthy don't contribute to a trial like this because they don't they have either no or very few events in the course of the trial, it's hard to get low.
Other than no events, obviously with your drug so they did recommend that we have patients who are more at risk of having events.
We think this will be valuable in thing the effect of the drug patients should be somewhat thicker that what we should say and all these trials the average.
<unk> tends to be around 2000, and all the trials.
Around where most patients sort of the most patient Saar, but we did want to have make an important that we can show a benefit for patients.
Thanks, David.
The next question comes from Myles Minter with William Blair. Please go ahead.
Good morning. This is correct me on for miles. We just had a quick question on will follow up some more phase one study and to the other ones.
Do you have any additional details on why do you accomplish southern shadows clinical measures of efficacy and what sort of like the follow up would be possible at all.
Can you talk about some of the clinical endpoints that we look forward to seeing from the phase one work in 'twenty one.
Okay, Yeah, none of the things that we looked at in this trial include Probie M P and MRI of the heart.
For most patients with cardiomyopathy, they have not reached our one year, yet and we're not yet giving guidance as to when that data will be available, but we do want to have data on the full cohorts of patients so that it's mature.
The next question.
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, Hey, congrats on the progress and thanks for taking the question. According to your models to what extent do you expect to further reduce cardiovascular events.
Including mortality with a deeper T. T are knocked down with 2001 relative to an RNA silencer. Thank you.
Yeah.
We haven't given a quantity quantity you can quantitate.
Reduction so that it's really hard to answer your question exactly there.
The next question comes from William occurring with Bernstein. Please go ahead.
Hi, Good morning. This is one of our wells will take our question could you provide any information on how the timeline for the magnitude of study aligned with your cash runway.
And how do you plan to keep investors interested in Colorado over the likely three to five year childcare yet thanks.
Glenn do you want to address our.
Our spend rates and runway sure yes. So thanks for the question, yes, so as we talked about the current Cashway will get us beyond the next 24 months.
We're not guiding specifically as to how how far people get into the study with the runway, but we will get pretty deep into the phase III just as a reminder, regeneron is subsidizing 25% of cost.
The next question comes from Silvan <unk> with JMP. Please go ahead.
Thank you and thanks for taking my question and congrats on the progress.
I just wanted to talk about or comment on the islands earnings call, where that's increasing switching problem, but just trying to participate in that and I I think it's most likely to the dosing regimen is there any read across to until you're at 21, okay.
Thank you.
Well this is John I'll take that.
Fundamental premise of what we're doing with 20 O. One is all about efficacy and.
We expect to show that with the studies that we've been discussing at length here today. So that's what drives physicians decisions primarily.
But it's also true that the patient experiences are key to what factors will take into consideration.
And I don't think it's any secret that.
Medications that are easy to take orders that are taken only a single time are going to be easier to take than folks that are infused or self.
Ministers or whatever so convenience certainly figures into this it's just part of 'twenty, one and as we look at 20 O two and the H HAE patient population, we've learned at that very much drives how those patients think about.
Taking their medicine, so it's an important aspect for sure.
The next question comes from David Leibowitz with Citi. Please go ahead.
Thank you for taking my question.
With respect to the 80 Chiara trial.
Given the potential enrollment timelines and the fact that there could be another stabilizer on the market and even potentially a TCR silence there on the market at some point in the future for cardiomyopathy.
How would you consider dealing with number one in the inclusion criteria for.
For patients on right now, which is just on task, but also for drop in patients that have subsequent point.
How would we deal with a potential trigger from Google in the future.
Yes, so for digital stabilizers are ones that official stabilizes make him available we will be able to modify the protocol to allow those patients into the trial.
For silent serves of course. This is this is a while off within the trial, but we do anticipate that some patients will go on for filing through some time in the trial and we have decided that into the trial as well.
Got it and jumping over to a T D N the insertion candidate.
Given the recent AD com when they certainly are focused a lot on.
Various risks associated with insertion.
Is there any particular nuance to the I N D and clinical process that needs to be considered.
With this approach versus a knockdown.
Maybe we can turn to Laura who can speak to.
Our unique.
Our approach is tough target analyses with an assertion candidate versus non insertion, Canada and just generally how we approach off targets versus what's been presented at the recent outcome.
Yeah, I'm not sure I. Thank you for the question so for any of them have already set the programs, whether it's <unk> or cut their mine.
God.
So as you've talked to the guy right. So.
Q3 than it did that was trained right. That's introduced baggage sympathetic that guide we send a guy that's doing the type of Scotty Cameron looking at one time.
And of course, you know, it's funny because the currency assumption here.
Core inflation, particularly in that side, but then you look more broadly but again. The goal you said this is a credit spread in the 18th Hershey and where it's going to be perfect.
Location for infections, and yes on the fastest time to power our Indiana.
Yeah.
Well, thank you for taking my questions.
The next question comes from seeds seed House with Raymond James. Please go ahead.
Hi, Good morning. This is Nick on for Steve I actually have a broader question related to Christopher's Exorcised Com, specifically do you have plans for patient level whole genome sequencing across any of your programs to value all sort of edits.
In future studies, given it was an interest for some of the panel members.
Oh, we don't that's not something that we think would be informative.
<unk> discussed extensively with regulatory agencies, who all concur and that assessment that takes the approach we've taken from how we look at off targets versus what was presented also differ probably figures into the thinking.
The next question comes from Whitney <unk> with Canaccord Genuity. Please go ahead.
Hi, Good morning, this is too long on for Whitney.
Thanks for taking our question Oh, well the magnitude trial also set sunshine points like six minute walk test is part of a secondary end points and I guess, what's your take on requiring who's well behind us.
David when we include six minute walk test as a secondary endpoint.
Six minute walk test will be an exploratory endpoint in our trial.
And second question.
Let's see utility of other secondary endpoints I think bush, but what else.
Yes.
Thank the most important secondary endpoints include quality of life is at a high level of interest that both of them.
Regulatory agencies as well as other places and it's well PPR levels reduction in Ctr will be important as a secondary endpoint.
Great. Thank you.
This concludes our question and answer session I would like to turn the conference back over to Ian Karp for any closing remarks.
Okay, well, thanks again, everyone for joining us.
We appreciate your time and we look forward to continuing to update you as we make further progress with our pipeline technologies have a great day everyone.
The conference has now concluded. Thank you for attending today's conference you may now disconnect.
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