Q3 2024 Intellia Therapeutics Inc Earnings Call

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.

Speaker Change: I will now turn the conference over to Lina Li Senior director of Investor Relations and corporate Communications at <unk>. Please proceed.

Good morning and welcome to Intellia Therapeutics' third quarter 2024 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.

Lina Li: Thank you operator, and good morning, everyone welcome to Empire Therapeutics third quarter 2024 earnings call.

Lina Li: Earlier this morning, <unk> issued a press release outlining the companys product this quarter as well as topics for discussion on today's call. This release can be found on the investors and media section of Italian website at <unk> Dot com.

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.

Lina Li: Call is being broadcast live and a replay will be archived on the Companys website.

At this time I would like to take a minute to remind listeners that during 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 a discussion of potential risks and uncertainties.

Drew: I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intelia. Please proceed.

All information presented on this call is current as of today and I'm, telling you. It undertakes no duty to update this information unless required by law.

Lina Li: Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics' third quarter 2024 earnings call.

Joining me from Italia are John Leonard Chief Executive Officer, David <unk>, Chief Medical Officer, Laurie <unk>, Chief Scientific Officer, and Ed <unk> Chief Financial Officer.

Drew: Earlier this morning, Intelli issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call.

Lina Li: John will begin with recent business highlights David will provide updates on our clinical pipeline progress. Laura will then provide R&D updates and Ed will review our financials before we open the call for questions with that I will now turn the call over to John <unk>, Our Chief Executive Officer.

Drew: This release can be found on the Investors & Media section of Intelia's website at www.inteliatx.com. This call is being broadcast live and a replay will be archived on the company's website.

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

John Leonard: Thank you Lena good morning, everyone and thank you all for joining us today.

John Leonard: I can tell you we are ushering in a new era of medicine things.

John Leonard: During the third quarter and more recent period, we have made substantial progress in our efforts to bring promising highly differentiated and potentially curative CRISPR based gene editing treatments to patients.

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

Drew: Joining me from Atelier are John Leonard, Chief Executive Officer, David Lebwohl, Chief Medical Officer, Laura Sepp-Lanzino, Chief Scientific Officer, and Ed Dulac, Chief Financial Officer.

John Leonard: In October at the American College of allergy asthma, and immunology annual scientific meeting we presented unprecedented positive results from our phase II study of until late 'twenty two for the treatment of hereditary angioedema.

Drew: John will begin with recent business highlights, David will provide updates on our clinical pipeline progress, Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer.

John Leonard: These results showed that a simple onetime infusion of MTL, a 20 O. Two offers patients the potential for a functional cure.

John: Thank you, Lena. Good morning, everyone, and thank you all for joining us today. At Intelia, we are ushering in a new era of medicine.

John Leonard: For people living with H E. Current treatment options are limited to chronically administered prophylactic therapies to prevent or manage the tax and the use of our on demand therapy to control breakthrough attacks because of this available therapies placed emphasis on attack rate reductions for their lifelong treatments.

John: During the third quarter and more recent period, we've made substantial progress in our efforts to bring promising, highly differentiated, and potentially curative CRISPR-based gene editing treatments to patients.

Drew: In October, at the American College of Allergy, Asthma, and Immunology Annual Scientific Meeting, we presented unprecedented positive results from our Phase 2 study of NTLA-2002 for the treatment of hereditary angioedema.

John Leonard: However, our market research is clear.

John Leonard: Patients want to lead a normal life when that is free of attacks, we have chronic treatment and free of mental burden around potential triggers and the loss of access to the therapies.

Drew: These results showed that a simple one-time infusion of NKLA-2002 offers patients the potential for a functional cure.

The emerging profile for until late 'twenty. Two provides hope that a single intervention may lead to a complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients the opportunity to deliver such a profile will create significant value for patients.

Drew: For people living with HAE, current treatment options are limited to chronically administered prophylactic therapy.

John Leonard: In the health care system as a whole.

John Leonard: We're extremely encouraged for our phase two results and we are actively screening patients in the phase III Halo study the strong enthusiasm for until late 'twenty two from patients and our investigators strengthens our conviction that the phase III will enroll rapidly enabling us to submit our planned BLA in 2000.

However, our market research is clear.

Drew: Patients want to lead a normal life, one that is free of attacks, free of chronic treatment, and free of mental burden around potential triggers and the loss of access to their therapies.

Drew: The emerging profile for NKLA-2002 provides hope that a single intervention may lead to the complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients.

Lina Li: 26.

Lina Li: In addition, we're making excellent progress across our other late stage trials as announced this morning, the FDA cleared our IND application for magnitude to a phase III trial of <unk> for patients with hereditary <unk> amyloidosis with Polyneuropathy, we expect to initiate.

Drew: The opportunity to deliver such a profile will create significant value for patients and the health care system as a whole.

Lina Li: The study in the coming days since dosing our first cardiomyopathy patient in March we continued to see strong momentum in our phase III magnitude study and enrollment is tracking ahead of our internal projections.

Speaker Change: We're extremely encouraged for our Phase 2 results, and we're actively screening patients in the Phase 3 HALO study. The strong enthusiasm for MTLA-2002 from patients and our investigators strengthens our conviction that the Phase 3 will roll rapidly.

Lina Li: With three active phase III study is expected by year end, we are leading the field of in vivo CRISPR based medicines and Telia is ushering in a new era of medicine with the prospect for a functional cure for patients suffering from HPE and a treatment that may change the course of the disease for people with <unk>.

enabling us to submit a plan BLA in 2026.

Speaker Change: In addition, we're making excellent progress across our other late-stage trials.

Drew: As announced this morning, the FDA cleared our I&D application for Magnitude 2 for Phase 3 trial of Nexi for patients with hereditary ATTR amyloidosis with polyneuropathy.

Lina Li: <unk> amyloidosis.

Speaker Change: 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.

Drew: We expect to initiate the study in the coming days. Since dosing our first cardiomyopathy patient in March, we continue to see strong momentum in our phase three magnitude study and enrollment is tracking ahead of our internal projections.

Speaker Change: Thanks, John.

Speaker Change: Begin with 20 O two in development for hereditary angioedema or H E.

Speaker Change: As John noted, we presented phase two data, which demonstrated that a single dose of 'twenty or two could both eliminated attacks and eliminate the need for further treatment in.

Drew: With three active Phase III studies expected by year end, we are leading the field of in vivo CRISPR-based medicines.

Speaker Change: And the 50 milligram arm eight of 11 patients had no attacks during the 16 week primary observation period. After a single dose of 20 O two.

Drew: Intelia is ushering in a new era of medicine with the prospect of a functional cure for patients suffering from HAE and a treatment that may change the course of the disease for people with ATTR amyloidosis.

Speaker Change: These groundbreaking results highlight how 'twenty or two has the potential to reset the standard of care for H E E.

Speaker Change: I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David. Thank you.

Speaker Change: We are encouraged by the findings are as far from the post primary observation period in the phase two as well.

Thanks, John.

Drew: I'll begin with 2002, in development for hereditary angioedema, or HAE.

Speaker Change: The eight patients who were attack free and the 50 milligram cohort remain attack free with no <unk> directed therapy for a median of eight months so far.

Drew: As John noted, we presented Phase 2 data which demonstrated that a single dose of 2002 could both eliminate attacks and eliminate the need for further treatment.

Speaker Change: Moreover, the three patients who are not yet attack free achieved clinically meaningful attack rate reductions.

Drew: In the 50 mg arm, 8 of 11 patients had no attacks during the 16-week primary observation period after a single dose of 2002.

Speaker Change: Based on our phase one observations when you expect these patients to show continued improvement or become attack free as they have more time to adjust to the new normal.

Drew: These groundbreaking results highlight how 2002 has the potential to reset the standard of care for HAE.

Speaker Change: We are continuing to follow all patients and look forward to presenting longer follow up data next year.

Drew: We are encouraged by the findings thus far from the post-primary observation period in the phase two as well.

Speaker Change: With 22, we believe we are creating a new standard for patient outcomes in <unk>.

Drew: The eight patients who are attack-free in the 50 milligram cohort remain attack-free with no HRE-directed therapy for a median of eight months so far.

Speaker Change: We're 12 out of 15 patients or 80% of patients who received the 50 milligram dose in the phase one two study appear functionally cured of their disease.

Drew: Moreover, the three patients who are not yet attack-free achieved clinically meaningful attack rate reductions.

Speaker Change: That is patients were attack free without the need for further treatment.

Speaker Change: This is unprecedented and suggest an emerging product profile that is unmatched by other HIV therapies, either currently approved or in development.

Drew: Based on our Phase I observations, we expect these patients to show continued improvement or become attack-free as they have more time to adjust to the new normal.

Speaker Change: Importantly, our market research indicates that 20 or twos emerging product profile aligns directly with the needs and priorities of patients and physicians.

Drew: We are continuing to follow all patients and look forward to presenting longer follow-up data next year.

Drew: With 2002, we believe we are creating a new standard for patient outcomes in HAE.

Speaker Change: As such we expect broad interest and demand for 'twenty or two that will drive rapid enrollment of our phase III study and commercial uptake once approved.

Drew: where 12 out of 15 patients or 80% of patients who receive the 50 milligram dose in the phase 1-2 study appear functionally cured of their disease. That is, patients were attack-free without the need for further treatment.

Speaker Change: We are now actively screening patients in the Halo phase III study, a global randomized double blind placebo controlled study.

Drew: This is unprecedented and suggests an emerging product profile that is unmatched by other HAE therapies either currently approved or in development.

Speaker Change: Accordingly, our phase II study will extend the primary observation period and look at the number of HCV attacks from weeks five through 28 as its primary endpoint.

Drew: Importantly, our market research indicates that 2002's emerging product profile aligns directly with the needs and priorities of patients and physicians.

Speaker Change: This is designed to provide a cleaner read into the drug's effects. Once collar crime reduction has reached a steady state about a month after therapy.

Drew: As such, we expect broad interest and demand for 2002 that will drive rapid enrollment of our Phase III study and commercial uptake once approved.

Speaker Change: As previously guided we expect to submit a BLA filing in 2026 from this 60 patient study.

Speaker Change: In summary, we believe 20 O two is well positioned to be the first approved in vivo CRISPR gene editing treatment and a truly transformative onetime treatment for people living with HIV.

Drew: We are now actively screening patients in the HALO Phase 3 study, a global randomized double-blind placebo controlled study.

Drew: Importantly, our phase 3 study will extend the primary observation period and look at the number of HAE attacks from weeks 5 through 28 as its primary endpoint.

Speaker Change: Switching to <unk> also known as 'twenty, one in development for the treatment of ATT amyloidosis.

Speaker Change: This multi system disease, primarily manifest I think their cardiomyopathy due to amyloid deposits in the heart.

Drew: This is designed to provide a cleaner read into the drug's effects once calocrine reduction has reached its steady state about a month after therapy.

Speaker Change: For Polyneuropathy through the progressive accumulation of protein deposits in the nervous system.

Speaker Change: We announced today that the U S. FDA cleared our IND application to initiate a phase III trial in patients with hereditary <unk> amyloidosis with Polyneuropathy.

Drew: In summary, we believe 2002 is well-positioned to be the first approved in vivo CRISPR gene editing treatment and a truly transformative one-time treatment for people living with HAE.

Speaker Change: This marks our fourth consecutive IMD clearance within 30 days of submission for in vivo therapies. We have developed an unparalleled regulatory track record in the field of gene editing and Testament to our high standards for drug development.

Drew: Switching to Nex-Z, also known as 201, in development for the treatment of ATTR amyloidosis.

Drew: This multi-system disease primarily manifests as either cardiomyopathy, through the amyloid deposits in the heart, or polyneuropathy, through the progressive accumulation of protein deposits in the nervous system.

Speaker Change: Our magnitude two phase III trial is an international randomized double blind placebo controlled study.

Speaker Change: 50 patients will be enrolled and randomized one to one to receive a single 55 milligram infusion of <unk> or placebo.

Drew: We announced today that the US FDA cleared our IND application to initiate a phase 3 trial in patients with hereditary ATTR amyloidosis with polyneuropathy.

Speaker Change: Patients randomized to the placebo arm will be eligible for optional crossover to receive next week.

Speaker Change: The primary endpoints are the change from baseline in this four seven at month 18, and serum C. T. R. At day 29.

Drew: This marks our fourth consecutive IMD clearance within 30 days of submission for in vivo therapies we have developed, an unparalleled regulatory track record in the field of gene editing and testament to our high standard for drug development.

Speaker Change: In Polyneuropathy, there's a positive correlation between greater T T our protein reduction and improved clinical benefit.

Drew: Our Magnitude II Phase III trial is an international, randomized, double-blind, placebo-controlled study.

Speaker Change: To date no other agent approved or in clinical development has demonstrated consistent deep and durable ctr reduction like Nexus, which gives us tremendous confidence in our ability to positively impact patient outcomes and the magnitude to study.

Drew: Fifty patients will be enrolled and randomized one-to-one to receive a single 55-milligram infusion of NEXE or placebo.

Drew: Patients randomized to the placebo arm will be eligible for optional crossover to receive next day.

Speaker Change: We expect to initiate the study at ex U S sites in the coming days.

Drew: The primary endpoints are the change from baseline in MNIST plus 7 at month 18 and serum TTR at day 29

Speaker Change: Simultaneously the rapid enrollment of the magnitude trial in patients with cardiomyopathy continues to track ahead of our internal projections based on strong patient and physician interest in.

Drew: In polyneuropathy, there is a positive correlation between greater TTR protein reduction and improved clinical benefit.

Speaker Change: In total we are actively enrolling patients at over 60 sites and have received regulatory clearance and more than 20 countries for the phase III study.

Drew: To date, no other agent approved or in clinical development has demonstrated consistent, deep, and durable TTR reduction like NEX-Z, which gives us tremendous confidence in our ability to positively impact patient outcomes in the MAGNITUDE 2 study.

Speaker Change: Findings in a recent publication of a competitor's clinical data and ATT RCM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide.

Drew: We expect to initiate the study at ex-U.S. sites in the coming days.

Speaker Change: In our ongoing phase one study, we demonstrated that all patients with cardiomyopathy achieved rapid deep and durable ctr reduction with next see.

Speaker Change: More consistent and greater mean reductions in that reported with TCR silences.

Speaker Change: As such our early clinical data suggests <unk> could significantly reduce total ctr exposures, which in turn might provide greater clinical benefit for patients.

Drew: In total, we are actively enrolling patients at over 60 sites and have received regulatory clearance in more than 20 countries for the Phase III study.

Drew: Findings in a recent publication of a competitor's clinical data in ATTRCM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide.

Speaker Change: Next Saturday November 16th we will be presenting new findings from the ongoing phase one study as a late breaking oral presentation at the American Heart Association scientific sessions.

Drew: In our ongoing Phase I study, we demonstrated that all patients with cardiomyopathy achieved rapid, deep, and durable TTR reduction with NEX-Z, more consistent and greater mean reductions than that reported with TTR silencers.

Speaker Change: On the occasion of <unk> hundredth anniversary, we will be presenting data at the opening session titled celebrating a century of cardiovascular science from prevention to treatment to cure.

Speaker Change: These data will provide insights into the emerging clinical profile of <unk> and the hypothesis that greater ctr reduction leads to better clinical outcomes.

Drew: As such, our early clinical data suggest NEXE could significantly reduce total TTR exposures, which in turn might provide greater clinical benefit for patients.

Speaker Change: The update will include data from all 36 patients within the cardiomyopathy arm, including important measures of clinical and functional benefit.

Speaker Change: This includes safety reduction of GTR and disease progression markers, such as empty pro BNP proponent six minute walk test at month 12 compared to baseline.

Drew: On the occasion of AHA's 100th anniversary, we will be presenting data at the opening session titled Celebrating a Century of Cardiovascular Science from Prevention to Treatment to Cure.

Speaker Change: We look forward to reviewing these data on an investor webcast, taking place that same day.

Speaker Change: We will also provide an update on the Polyneuropathy arm.

Drew: These data will provide insights into the emerging clinical profile of MECC-C and the hypothesis that greater TTR reduction leads to better clinical outcomes.

Speaker Change: I'll now hand, the call over to Laura our Chief Scientific Officer, who will provide updates on the 30th one program and our R&D efforts.

Laura: Thank you David Good morning, everyone, we're advancing our science and even local therapy and into our first in vivo gene insertion programs seem to Kenny and then they sort of get one it's our first wholly owned in vivo gene correction program for Alpha one antitrypsin deficiency associated Languishes EPC sign.

Drew: This includes safety, reduction of TTR, and disease progression markers such as NT-ProBNP, troponin, 6-minute Watt test at month 12, compared to baseline.

Speaker Change: To precisely Thursday, wild type therapy, a one gene, which encodes the alpha one Antitrypsin project.

Drew: We look forward to reviewing these data on an investor webcast taking place that same day where we will also provide an update on the polyneuropathy arm.

Speaker Change: And previously presented non human primate data, we've demonstrated the ability to produce fully functional alpha one protein at Noah.

Speaker Change: I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the 3001 program and our R&D efforts.

Speaker Change: Demand levels after a single dose.

Speaker Change: Notably these normal levels.

Speaker Change: Were durable through two years in front of lap in the completed study.

Speaker Change: We're on track to dosing the first patient in the phase one two study of 31 by year end.

Speaker Change: We're able to translate what we have seen in nonhuman primates to humans. We believe this will be a major step forward for alpha one patients in the field of gene editing.

Speaker Change: Assuming success.

Laura Sepp-Lanzino: It is designed to precisely insert the wild-type serpent A1 gene, which encodes the alpha-1 antitrypsin protein.

Speaker Change: Okay, holding you category FCC states, which require a gain of function that we could pursue with our marginally assertion that for them.

Laura Sepp-Lanzino: In previously presented non-human primate data, we've demonstrated the ability to produce fully functional alpha-1 protein at normal levels after a single dose.

Speaker Change: In parallel we're continuing to advance our toolbox of novel Gene editing and delivery technologies to extend the reach of CRISPR based gene editing for it'll be evil and ex vivo therapeutic applications. This includes advancing gene editing programs.

Speaker Change: We're on track to dose the first patient in the Phase I-II study of 30.1 by year end.

Speaker Change: Different tissues outside the liver either independently or in collaboration with partners.

Speaker Change: If we're able to translate what we have seen in non-human primates to humans, we believe this will be a major step forward for Alpha-1 patients and the field of gene editing.

Speaker Change: We're proud of all the recent crisis and look forward to providing more updates as we advance our platform and pipeline.

Speaker Change: I'll now hand over the call to and our Chief Financial Officer, who will provide an update on our financial results as of third quarter 'twenty three for them.

Speaker Change: Assuming success, it would unlock a whole new category of diseases which require a gain of function that we could pursue with our modular insertion platform.

Speaker Change: Thank you Laura and good morning, everyone.

Speaker Change: In parallel, we're continuing to advance our toolbox of novel gene editing and delivery technologies to extend the reach of CRISPR-based gene editing for in vivo and ex vivo therapeutic applications.

Speaker Change: <unk> continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform.

Speaker Change: Our cash cash equivalents and marketable securities were approximately $944 7 million as of September 32024.

Speaker Change: This includes advancing gene editing programs in five different tissues outside the liver, either independently or in collaboration with partners.

Speaker Change: Compared to $1 billion as.

Speaker Change: We're proud of all the recent progress and look forward to providing more updates as we advance our platform and pipeline.

Speaker Change: As of December 31, 2023.

Speaker Change: The decrease was driven by cash used to fund operations of approximately $335 million.

Speaker Change: I now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of third quarter 2024.

Speaker Change: The decrease was offset in part by $176 9 million of net equity proceeds from the company's aftermarket program.

Thank you, Laura, and good morning, everyone.

Speaker Change: Intelia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform.

Speaker Change: $47 million of collaborator reimbursements, including a one time $30 million payment received in April related to the Companys technology collaboration with Regeneron.

Speaker Change: Our cash, cash equivalents, and marketable securities were approximately $944.7 million as of September 30, 2024, compared to $1 billion as of December 31, 2023.

Speaker Change: $37 $2 million of interest income.

Speaker Change: $6 5 million and proceeds from employee based stock plan.

Speaker Change: Our collaboration revenue was $9 1 million during the third quarter of 2024 compared.

Speaker Change: The decrease was driven by cash-use-to-fund operations of approximately $335 million.

Speaker Change: Compared to $12 million during the third quarter of 2023.

Speaker Change: The decrease was offset in part by $176.9 million of net equity proceeds from the companies at the market program.

Speaker Change: The $2 $9 million decrease was mainly driven by a reduction in revenue related to the advent of license and collaboration agreement.

Speaker Change: $47 million of collaborator reimbursements including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron.

Speaker Change: R&D expenses were $123 4 million during the third quarter of 2024 compared to $113 $7 million during the third quarter of 2023.

Speaker Change: $37.2 million of interest income and $6.5 million in proceeds from employee-based stock plans.

Speaker Change: The $9 7 million increase was primarily driven by the advancement of our lead programs.

Speaker Change: Our collaboration revenue was $9.1 million during the third quarter of 2024, compared to $12 million during the third quarter of 2023.

Speaker Change: Stock based compensation included in R&D expense was $24 2 million for the third quarter.

Speaker Change: G&A expenses were $30 5 million during the third quarter of 2024 <unk>.

Speaker Change: The $2.9 million decrease was mainly driven by a reduction in revenue related to the Abincel License and Collaboration Agreement.

Speaker Change: Compared to $29 $4 million during the third quarter of 2023.

Speaker Change: R&D expenses were $123.4 million during the third quarter of 2024, compared to $113.7 million during the third quarter of 2023.

Speaker Change: The $1 $1 million increase was primarily related to stock based compensation.

Speaker Change: Stock based compensation included within G&A expense was $15 4 million for the third quarter of 2024.

Speaker Change: The $9.7 million increase was primarily driven by the advancement of our LEAD programs.

Speaker Change: Finally, we expect our cash balance to fund our operating plan until late 2026.

Speaker Change: Stock-based compensation included in R&D expense was $24.2 million for the third quarter.

Speaker Change: Thanks, Ed and.

Speaker Change: In conclusion, and Kelly continues to deliver on the promise of gene editing and we look forward to presenting the next see phase one update next week at IHA.

Speaker Change: G&A expenses were $30.5 million during the third quarter of 2024, compared to $29.4 million during the third quarter of 2023.

Speaker Change: With that we will now open the call for your questions to do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

The $1.1 million increase was primarily related to stock-based compensation.

Speaker Change: We will now begin the question and answer session.

Speaker Change: The stock-based compensation included within G&A expense was $15.4 million for the third quarter of 2024.

Speaker Change: Ask a question you May press Star then one on your Touchtone phone.

Speaker Change: If you're using a speaker phone. Please limit your handset excuse me please pickup your handset before pressing the keys.

Speaker Change: Finally, we expect our cash balance to fund our operating plans into late 2026.

Thanks, Ed.

Speaker Change: Your question. Please press Star then two please limit yourself to one question.

Speaker Change: In conclusion, Intellia continues to deliver on the promise of gene editing, and we look forward to presenting the next phase 1 update next week at AHA.

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

Speaker Change: First question comes from Rick and Koski with Cantor Fitzgerald. Please go ahead.

Speaker Change: With that, we will now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

Speaker Change: Hey, good morning, and thank you for taking the question I was just hoping to get more color on the pace of enrollment into magnitude one.

We will now begin the question and answer session.

Speaker Change: Just looking at the clinical trial record on clinical trials Dot Gov. The estimated primary completion has worked with us.

Speaker Change: To ask a question, you may press star then 1 on your touchtone phone.

Speaker Change: December 2027, so could you just walk me through the assumptions there for the pace of enrollment given that the primary endpoint is event driven.

Speaker Change: If you are using a speakerphone, please pick up your handset before pressing the keys.

Speaker Change: To withdraw your question, please press star then 2. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster.

Speaker Change: Thanks for the question Rick.

Speaker Change: As we've said.

Speaker Change: You can use.

Speaker Change: <unk> study is a really good proxy with similar assumptions.

Speaker Change: The first question comes from Rick Bienkowski with Cancer Fitzgerald. Please go ahead.

Speaker Change: That the study has 765 patients.

Speaker Change: We have global sites activated in the final sites will be activated as we speak here. So as we said in our comments here.

Rick Bienkowski: Hey, good morning, and thank you for taking the question. I was just hoping to get more color on the pace of enrollment into Magnitude I. Just looking at the clinical trial record on clinicaltrials.gov, the estimated primary completion is listed at

Speaker Change: We're enrolling ahead of our projections.

Speaker Change: And as we get further insight there may be an opportunity to update that down the road, but in the Meanwhile, things are progressing very very well.

Rick Bienkowski: December 2027. So could you just walk me through the assumptions there for the pace of enrollment given that the primary endpoint is event-driven?

Speaker Change: The next question comes from Alec Stranahan with Bank of America. Please go ahead.

Thanks for the question, Rick. As we've said,

Speaker Change: You can use the Helios study as a really good proxy with similar assumptions. You know that the study has 765 patients.

Speaker Change: Hey, guys. This is Matthew on for Alex Thanks for taking our question just one quick one for us.

Speaker Change: You think about extending into later stage clinical trials, just thinking about your capital allocation priorities given that you have a lot going on in the pipeline and sort of how youre thinking about in vivo versus ex vivo going forward.

Speaker Change: We have global sites activated and the final sites are being activated as we speak here.

Speaker Change: So, as we said in our comments here, we're enrolling ahead of our projections and as we get further insight, there may be an opportunity to update that down the road, but in the meanwhile, things are progressing very, very well.

Speaker Change: So maybe Ed can address that.

Speaker Change: We will follow up as necessary.

Speaker Change: Yes. Thanks for the question I mean, we exited the third quarter about $945 million in cash and.

Speaker Change: As we look out at our two or three year plan I think we've laid out at Jpmorgan earlier. This year three year priorities strategic priorities through 2020 six so as I look at the company today, we clearly have a focus on the three phase III studies, which will be up and running before the end of the year and that's clearly a focus we do have some exciting programs related to <unk>.

Speaker Change: The next question comes from Alec Stranahan with Bank of America. Please go ahead.

Speaker Change: 101, our first gene insertion program, which is an important proof of concept for us as well as sort of burgeoning ex vivo opportunities as well and then we've been very prominent and just investing across the platform. So.

Speaker Change: So maybe Ed can address that and we'll follow up as necessary.

Speaker Change: Look at our existing cash burn at roughly $100 million over the last couple of quarters is a reasonable estimate that should go up but I feel like we have a very conservative plan in place one that it takes our existing cash balance and gets us well into our fourth quarter of 2026.

Ed Dulac: As we look at our two- or three-year plan, I think we've laid out at J.P. Morgan earlier this year, three-year priorities, strategic priorities through 2026, and so

Speaker Change: As I look at the company today, we clearly have a focus on the three phase three studies, which will be up and running before the end of the year, and that's clearly a focus.

Speaker Change: The next question comes from Yanan, Zhu with Wells Fargo Securities. Please go ahead.

Speaker Change: We do have some exciting programs related to 30.01, our first gene insertion program, which is an important proof of concept for us, as well as sort of burgeoning ex vivo opportunities as well. And then we've been very prominent in just investing across the platform.

Speaker Change: Great. Thanks for taking our questions.

Speaker Change: Wondering first congrats on the clearance from FDA to conduct the phase III study in <unk> Polyneuropathy.

Speaker Change: Just struck by two things from the trial design.

Speaker Change: I look at our existing cash burn at roughly, you know, $100 million over the last couple quarters. As a reasonable estimate, that should go up. But I feel like we have a very conservative plan in place, one that takes our existing cash balance and gets us well into fourth quarter of 2026.

Speaker Change: Is that it is.

Speaker Change: A placebo controlled study and not.

Speaker Change: Silent for example, active arm controlled study and the other is that the patient studies science is a very small 50 patients that's not even half of.

Speaker Change: The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.

Speaker Change: The size of the Silencer studies, so could you comment on.

Speaker Change: This.

Speaker Change: The.

Speaker Change: The ability to obtain.

Speaker Change: Obtaining such a study design.

Speaker Change: And what does it mean and also.

Yanan Zhu: I was just struck by two things from the trial design. One is that it is a placebo-controlled study and not a clinical trial.

Speaker Change: Patients on the.

Speaker Change: Either arm allowed to receive.

Speaker Change: Silence or or other active treatment during the study. Thank you.

Speaker Change: So thanks for the question.

Speaker Change: silent, for example, active arm control study. And the other is that the patient, the study size is very small. Safety patients, that's not even half of the size of the silencer studies.

Speaker Change: First of all it's important to note that the effect size of <unk> reduction is very very large <unk> patients with polyneuropathy that's been established.

So, could you comment on...

Speaker Change: We have pretty good insight as to the effects as a function of TCR reduction and as we've shared elsewhere. Our ctr reduction is profound.

Speaker Change: obtained such a study design, what does it mean, and also, will patients on either arm allowed to receive silencer or other active treatment during the study? Thank you.

Speaker Change: And we expect that to continue into this patient population in phase III.

Speaker Change: A placebo controlled trial as possible based on our agreement with the FDA and other regulatory agents it will.

Speaker Change: Give us a very solid readout on the performance and safety of the drug.

Speaker Change: So thanks for the question. First of all, it's important to note that the effect size

Speaker Change: And by carrying it out outside the United States, where many of these other therapies are not currently available. It allows the study to be enrolled promptly and we'll be in a position to share the data when we have it.

Speaker Change: of TTR reduction is very, very large in patients with polyneuropathy. That's been established.

We have...

Speaker Change: And David you can speak to any other details that you think are pertinent to that study or silences.

Speaker Change: Pretty good insight as to the effects as a function of TTR reduction.

Speaker Change: And as we've shared elsewhere, our TTR reduction is profound. And we expect that to continue into this patient population.

David: Yeah. Thank you John.

David: Think what Youre seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward. All the other drugs have been approved with placebo controlled study or studies. So that makes a lot of sense as well for our drug.

Page 3

Speaker Change: give us a very solid readout on the performance and safety of the drug.

David: And again silences.

David: Not available in the country, where the studies are being conducted so patients will not be receiving silences.

Speaker Change: And by carrying it out outside the United States, where many of these other therapies are not currently available, it allows the study to be enrolled promptly and we'll be in a position to share the data when we have it.

Speaker Change: Got it thank you.

Speaker Change: The next question comes from Mani <unk> with Leerink. Please go ahead.

Speaker Change: and David you can speak to any other details that you think are pertinent to that study or silencers.

Speaker Change: Hi, Good morning, this is CJ on for money.

David: Question is regarding the <unk>.

David Lebwohl: Thank you, John. You know, I think what you're seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward. All the other drugs have been approved with placebo-controlled study, so that makes a lot of sense as well for our drug.

David: Phase III Halo study it just notice that patients are randomized two to one there versus one to one in magnitude. So I was just wondering if you thought the student enrollment was.

David: Start to accelerate patient enrollment in the study thank you.

David Lebwohl: And again, silencers are not available in the country where the studies are being conducted, so patients will not be receiving silencers.

Speaker Change: David do you want to speak to the randomization scheme.

David: Yes, the benefit of a two to one randomization is for the patients themselves and it's attractive to them that they'll have two thirds chance to start on the active drug right away. They also all these patients will be able to cross over if they wish as well at the end of the primary observation period. So it is.

Got it. Thank you.

Speaker Change: The next question comes from Mani Foroohar with Lyrinc. Please go ahead.

CJ: Hi, good morning. This is CJ on Furmani. My question is regarding the...

CJ: Phase III Halo study I, just noticed that patients are randomized two to one there versus one to one in magnitude. So I was just wondering if you thought the student enrollment was thought.

CJ: Phase 3 HALO study, I just noticed that patients are randomized 2 to 1 there.

David: Also attractive to patients for that reason with all that in place. We do anticipate very rapid enrollment as we saw in the phase II as well.

CJ: versus one-to-one in magnitude, so I was just wondering if you thought this two-to-one enrollment was thought to accelerate patient enrollment in the study. Thank you.

David: The number of patients.

CJ: Got to accelerate patient enrollment in the study thank you.

David: By having two to one also you have more information on the active arm is <unk>.

Speaker Change: David do you want to speak to the randomization scheme.

David, do you want to speak to the randomization scheme?

Speaker Change: Part of it.

David: BLA submission that will be coming up in 2026.

David Lebwohl: Yes, the benefit of a two to one randomization is is for the patients themselves and it's attractive to them that they'll have two thirds chance to start on the active drug right away. They also all these patients will be able to cross over if they wish as well at the end of the primary observation period. So it's also.

CJ: Yeah, the benefit of a two-to-one randomization is for the patients themselves. It's attractive to them that they'll have two-thirds chance to start on the active drug right away.

Speaker Change: The next question.

Speaker Change: The next question comes from cost of Dolores with BMO capital markets. Please go ahead.

David Lebwohl: They also, all these patients will be able to cross over if they wish, as well at the end of the primary observation period. So it's also attractive to patients for that reason. With all that in place, we do anticipate very rapid enrollment as we saw in the phase two as well.

Speaker Change: Good morning, everyone and thanks for taking our question in vehicle catch on the progress one question for milestone the ATB program given that the gene that you insert it even under the control of the natural promote their app.

David Lebwohl: Attractive to patients for that reason with all that in place we do anticipate very rapid enrollment as we saw in <unk>.

David Lebwohl: Phase II as well.

David Lebwohl: The number of patients.

Speaker Change: And then in fact student facing to need about two to three times more a pea protein can you remind us how do you ensure that these additional AAP protein is that you are seeing infections. Thank you.

David Lebwohl: The number of patients, you know, by having two-to-one also, you have more information on the active arm as part of the VLA submission that will be coming up in 2026.

David Lebwohl: By having two to one also you have more information on the active arm.

David Lebwohl: As part of that.

David Lebwohl: L. A submission that will be coming up in 2026.

David Lebwohl: Yes.

Speaker Change: Okay.

David Lebwohl: The next question.

Speaker Change: Thanks for the question cost us.

The next question.

Speaker Change: The next question comes from Costar, Dolores with BMO capital markets. Please go ahead.

Speaker Change: We base our excitement over the Alpha one program on the preclinical.

David Lebwohl: The next question comes from Costas Velouris with BMO Capital Markets. Please go ahead.

Costas Velouris: Good morning, everyone and thanks for taking a question in the cold cuts on the progress one question for milestone the ATB program given that the gene that you insert it even under the control of the natural promote there and I'm getting fixed soon facing to need about two to three times more.

Speaker Change: Where.

Speaker Change: Good morning, everyone. Thanks for taking our question and congrats on the progress. One question from us on the AATB program.

Speaker Change: As you point out.

Speaker Change: Natural transgene is driven by the albumin promoter and with that in non human primates, we've achieved normal levels of the protein.

David Lebwohl: Given that the gene that you inserted isn't under the control of the natural promoter,

Speaker Change: Not expect that to be logical.

David Lebwohl: And under infection, patients need about two to three times more AAT protein. Can you remind us how do you ensure that this additional AAT protein is there during infections? Thank you.

David Lebwohl: P protein can you remind us how do you ensure that these additional AAP protein is that during infections. Thank you.

Speaker Change: The typical response to infection, because it'll be driven by the argument.

Speaker Change: Promoter.

Speaker Change: But what we prioritize these normalizing the protein because its primary it's the primary defect in patients with the disease.

David Lebwohl: Yeah.

Speaker Change: Thanks for the question cost us.

David Lebwohl: Thanks for the question Costas. We base our excitement over the Alpha-1 program on the preclinical

David Lebwohl: We base our excitement over the Alpha one program on the preclinical.

Speaker Change: <unk>.

Speaker Change: We think that that's going to be the primary determinant of the success of the product.

David Lebwohl: Where.

have, where...

David Lebwohl: As you point out.

Speaker Change: As you point out, the natural transgene is driven by the albumin promoter, and with that and non-human primates, we've achieved normal levels of the protein. I would not expect that to be...

David Lebwohl: Natural transgene is driven by the albumin promoter and with that in non human primates, we've achieved normal levels of of the protein.

Speaker Change: The next question comes from Joseph <unk> with <unk>.

Speaker Change: TD Cowen. Please go ahead.

Speaker Change: Hi, there good morning, Congrats on the progress and thank you for taking my question, maybe just on the magnitude to study.

Speaker Change: I would not expect that to be agile.

Speaker Change: The typical response to infection, because it'll be driven by the albumin.

Speaker Change: The GTR serum reduction is going to be a day 29 read and the Mrs. 18 months are you able to take a look at serum ctr.

David Lebwohl: the typical response to infection because it would be driven by the albumin promoter.

David Lebwohl: Promoter.

David Lebwohl: But what we prioritize these normalizing the protein because its primary it's the primary defect patients with the disease.

Speaker Change: Ahead of that 18 month time point.

David Lebwohl: but what we've prioritized is normalizing the protein because it's primary, it's the primary defect in patients with the disease and we think that that's going to be the primary determinant of the success of the product.

Speaker Change: While maintaining some sort of blind or should we anticipate both of those readouts coming at once and then secondly on <unk>.

David Lebwohl: And.

Speaker Change: Submission for Pn, how much does the submission in Pn dependent also success in magnitude one for CMO or are these completely uncoupled. Thank you.

David Lebwohl: We think that that's going to be.

David Lebwohl: The primary determinant of the success of the product.

Speaker Change: The next question comes from Joseph told me with.

Speaker Change: Maybe I can address that David can fill in blanks.

The next question comes from Joseph Thome with...

Speaker Change: TD Cowen. Please go ahead.

P.D. Cowan, please go ahead.

Speaker Change: The two programs neuropathy and cardiomyopathy are independent of each other and they are determined by the study designs in each of those particular indications we've talked earlier on the call here about cardiomyopathy program and how to think about that Polyneuropathy program is.

Joseph Thome: Hi, there good morning, Congrats on the progress and thank you for taking my question, maybe just on the magnitude to study as the GTR serum reduction is going to be a day 29 read and the Mrs. 18 months are you able to take a look at serum GTR.

David Lebwohl: Take a look at serum TTR ahead of that 18-month time point while maintaining some sort of blind or should we anticipate both of those readouts coming at once.

Joseph Thome: Ahead of that 18 month time point.

Joseph Thome: While maintaining some sort of blind or should we anticipate both of those readouts coming at once and then secondly on a.

Speaker Change: As was pointed out we will have an 18 month observation period in.

Speaker Change: In time sort of a landmark design.

David Lebwohl: And then secondly, on a submission for PN, how much does the submission in PN depend on also success in Magnitude 1 for CM or are these completely uncoupled? Thank you.

David Lebwohl: Our submission for Pn, how much does this emission N P and dependent also success in magnitude one for CMO or are these completely uncoupled. Thank you.

Speaker Change: But the two are independent of each other we would expect that <unk> will be supplementary from each of the programs as data accumulates, but in terms of the efficacy read they're entirely independent.

Speaker Change: Maybe I can address that and David can fill in the blanks.

Speaker Change: Maybe I can address that and David can fill in blanks.

Speaker Change: <unk>.

Speaker Change: The study is blinded and we will not be in a position that would be sharing data prematurely before the complete data readout. So don't look for GTR and then the ultimate clinical outcomes. It would be the full set of data as it becomes available David if you have anything to add to that.

Speaker Change: The two programs on neuropathy and cardiomyopathy are independent of each other and they're determined by the study designs in each of those particular indications we've talked earlier on the call here about the cardiomyopathy program and how to think about that Polyneuropathy program is.

Speaker Change: The two programs, polyneuropathy and cardiomyopathy, are independent of each other and are determined by the study designs in each of those particular indications. We talked earlier on the call here about the cardiomyopathy program and how to think about that.

Speaker Change: Yes.

Speaker Change: Yes, just to add to the observation that you've seen in our data that all patients have a major reduction in <unk>. So we won't be looking at that data. What we know from our experience is that all patients will be able to achieve a rapid and deep reduction in ctr and that that is maintained.

Speaker Change: The polyneuropathy program, as was pointed out, will have an 18-month observation period that's set in time, sort of a landmark design.

Speaker Change: That was pointed out we will have an 18 month observation period in.

Speaker Change: In time sort of a landmark design.

David Lebwohl: but the two are independent of each other. We would expect that safety will be supplementary from each of the programs as data accumulates, but in terms of the efficacy read, they're entirely independent.

Speaker Change: Probably permanently as far as we know, but certainly over two years at this point so.

David Lebwohl: The study is blinded, and we will not be in a position where we'll be sharing data prematurely before the complete data readout.

Speaker Change: We will see that at the time of unwinding as John says and.

Speaker Change: Pretty much know what to expect in that data.

David Lebwohl: So don't look for TTR and then the ultimate clinical outcomes, it will be the full set of data as it becomes available.

Speaker Change: Thank you.

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

Speaker Change: David, if you have anything to add to that, be my guest.

David Lebwohl: I'll just add to the observation that you've seen in our data that all patients have a major reduction in TTR.

Speaker Change: Hi, its Tony on for Gena. So on ACP art can you remind us of your assumptions for it sounds you're dropping rate and any strategies to address it if it ends up being higher than expected.

Speaker Change: So, though we won't be looking at that data, what we know from our experience is that all patients will be able to achieve a rapid and deep reduction in TTR, and that that is maintained probably permanently as far as we know, but certainly over two years at this point. So, thank you. Thank you.

Speaker Change: David do you want to speak to silence your trucking right.

Speaker Change: Yes, we have figure that into our trial, we haven't given the exam.

Speaker Change: The exact way that will happen, we should mention we think it's less likely now that we've seen the helios data that they will be much drop in what we've seen is.

Speaker Change: We will see that at the time of unblinding, as John says, and we pretty much know what to expect in that data.

Speaker Change: That there is some addition to PTR two.

Speaker Change: The family and that trial, but probably not enough to justify payers to pay for both drugs together.

Speaker Change: So we expect to see is that patients will continue on their families and our study they possibly may switch to nutrition.

Speaker Change: Payers allow that but even that switch we don't think will have any effect on our primary endpoint.

Speaker Change: Got it thank you.

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

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

Speaker Change: I was wondering if you could just talk more about how you're setting expectations for the IHA update for Biomarkers in a relationship or correlation to functional capacity Im wondering if youll show individual patient data potentially cardiac remodeling or imaging data as well.

Speaker Change: We expect to see is that patients will continue on their families and our study they possibly may switch to neutral surrender payers allow that but even that switch. We don't think will have any effect on our primary endpoint.

Speaker Change: I think I can start with that.

Speaker Change: Question and David can fill in some additional information.

Speaker Change: As we sit in our comments, we're very enthusiastic about sharing the data at the upcoming <unk> meeting and we're honored to be featured in the opening session of the meeting which.

Speaker Change: Got it thank you.

Speaker Change: It's something that.

Speaker Change: <unk> is addressing the next the century of cardio cardiac therapies and we're very very excited to be a part of that.

Speaker Change: As we've long said, we will share biomarker data functional data and clinical information on these patients and in terms of how we think about that meaning of that information.

Speaker Change: First we're excited about what we see because it relates for the first time the extent of the TTM reduction that we're achieving with those particular readouts and we think it will yield real insights into how we think about.

Speaker Change: The maintenance study and how we expect that.

Speaker Change: The drug to perform in that particular study.

Speaker Change: David if you want to share any other comments.

Speaker Change: Yeah, Justin as you see the data on November 16th.

Speaker Change: Recall that in the recent phase III is the active arms continued to show worsening in terms of these biomarkers BMP.

Speaker Change: <unk> continues to rise six minute walk continues to go down even though they are better than placebo, they're still worsening in the population as a whole seems important to observe as you see our data. Our data is also very robust test of this.

Speaker Change: Ability of deep GTR reductions to make a big clinical difference and thats, because 50% of our patients with class III instead of a 10% or so you'll see in the other studies and a full 31% of the patients have variant disease, which is really the very aggressive disease.

Speaker Change: And <unk> net those patients.

Speaker Change: As well in the other studies in around 10% to 12% so.

Speaker Change: So you will be seeing all 36 patients in the study because they've reached all reached one year and you will see the data for these patients comparing baseline to one year.

Speaker Change: Got it thanks for taking my question.

Speaker Change: The next question comes from Ryan <unk> with Guggenheim. Please go ahead.

Speaker Change: Hi, This is ray from Deb gets team what factors do you think are the major contributors to enrollment being ahead of schedule in the magnitude ATT RCM study and do you think these factors apply to magnitude to four P. M.

Speaker Change: What investigators tell us is they have been.

Speaker Change: Extremely excited with the extent of the <unk> reduction and the safety profile that they see with the drug to the states.

Speaker Change: We've seen confirmation with competitor programs that lowering GTR is meaningful for patients and the deep consistent and.

Speaker Change: Enduring.

Speaker Change: Reductions that we've achieved with the drug thus far I think is really excited.

Speaker Change: <unk>.

Speaker Change: Treating physicians around the world.

Speaker Change: We would anticipate that this will apply also to the magnitude study.

Speaker Change: Recall that many of these countries. This kind of therapy is not available for patients generally speaking and we know that there is great enthusiasm with all of the sites that we've spoken to.

Speaker Change: Extremely excited with the extent of the TCR reduction and the safety profile that they see with the drug to the states.

Speaker Change: We've seen a confirmation with competitor programs that lowering GTR is meaningful for patients and the deep consistent and enduring.

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

Speaker Change: Hey, great. Good morning, Thanks for taking our questions and congrats on the progress question on AA TD, just thinking about the phase one that's going to embark by the end of the year. If you can comment on any flexibility in that trial protocol to include any liver disease patients I know that was supposed to be more of a 2003 per.

Speaker Change: Reductions that we've achieved with the drug thus far I think is really excited.

Speaker Change: Treating physicians around the world.

Speaker Change: We would anticipate that this will apply also to the magnitude study.

Speaker Change: Recall that many of these countries. This kind of therapy is not available for patients generally speaking and we know that there was great enthusiasm with all the sites that we've spoken to.

Speaker Change: Review, but given the biology and the potential say facilitation of polymer excretion from the cells. Once you have more M protein. Just wondering if you can add in a little bit of that Sentinel cohort. If you will just to see the benefit there. Thanks so much.

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

Speaker Change: David the process, including liver disease in the 31 trial.

Speaker Change: Hey, great. Good morning, Thanks for taking our questions and congrats on the progress a question on a T. D. Just thinking about the phase one that's gonna embark by the end of the year. If you can comment on any flexibility in that trial protocol to include any liver disease patients I know that was supposed to be more of a 2003 per.

Speaker Change: These patients will not be having.

Speaker Change: Major any kind of major liver disease.

Speaker Change: Those patients with liver disease really are best addressed by reducing the mutant protein as well as of course, given the increased alpha one antitrypsin would be valuable to them as well, but without our ability to reduce the Z protein. We don't think were doing them for justice.

Speaker Change: Our view, but given the biology and the potential say facilitation of polymer excretion from the cells are once you have more M protein. Just wondering if you can add in a little bit of that Sentinel cohort. If you will just to see the benefit there. Thanks so much.

Speaker Change: The next question.

Speaker Change: Well just to add.

Speaker Change: At <unk> we.

Speaker Change: We're taking a.

Speaker Change: Expanded approach to going after Alpha one and in addition to 31, which we think.

Speaker Change: David the process, including liver disease in the 31 trial.

Speaker Change: So these patients will not be having a <unk>.

Speaker Change: We will teach us a lot about.

Speaker Change: Major any kind of major liver disease.

Speaker Change: Assertion approach for Alpha one disease and reads to multiplicity of other diseases for which assertion maybe the path forward. We're also bringing forward a gene writing program that would address underlying lung, but also deliver.

Speaker Change: Those patients with liver disease really are best addressed by reducing the mutant protein as well as of course, given the increased alpha one antitrypsin would be valuable to them as well, but without our ability to reduce the Z protein. We don't think we're doing the full justice.

Speaker Change: Okay.

Speaker Change: Next question comes from Luca <unk> with RBC. Please go ahead.

Speaker Change: The next question.

Speaker Change: Well just to add.

Speaker Change: Oh, great. Thanks, so much for taking our question. This is Lee.

Speaker Change: Okay.

Speaker Change: At <unk> we.

Speaker Change: So Luca congrats on all the progress your team and getting the IMD cleared for GTR Polyneuropathy. Just one question on the on the study I know the primary endpoint is and NIF plus 7% 18 months.

Speaker Change: We're taking a.

Speaker Change: Extended approach to going after al for one and in addition to 31, which we think.

Speaker Change: We will teach us a lot about it.

Speaker Change: Assertion approach for Alpha one disease and reads to multiplicity of other diseases for which insertion maybe the path forward. We're also bringing forward achieved writing program that would address underlying lung, but also deliver.

Speaker Change: However, I believe on an island was able to file in just nine months of follow up.

Speaker Change: Just curious if the 18 month endpoint was mostly needed to satisfy European regulators or did the FDA also request the longer follow up any color here would be helpful. Thanks, So much.

Speaker Change: Okay.

Speaker Change: David any comments to share on 18 months versus a different follow up time.

Speaker Change: Next question comes from Luca <unk> with RBC. Please go ahead.

David: Yes, we felt 18 months was looking at their trials, we felt up to 18 months was the optimal time to really see the full benefit of the drug.

Speaker Change: Oh, great. Thanks, so much for taking our question. This is Lisa on for Luka. Congrats on all the progress your team and getting the IMD cleared for T. T. R. Polyneuropathy.

Speaker Change: It was not required by regulators, but it was it was really our own decision to do that.

Speaker Change: Just one question on the on the study I know the primary endpoint is and Nif's plus seven at 18 months.

Speaker Change: The next question comes from Celgene Richter with Goldman Sachs. Please go ahead.

Speaker Change: However, I believe on island was able to file in just nine months of follow up.

Speaker Change: Just curious if the 18 month endpoint was mostly needed to satisfy European regulators or did the FDA also request the longer follow up any color here would be helpful. Thanks, So much.

Speaker Change: Hi, This is mark on for solving a first congrats on the quarter and thank you for taking our questions.

Speaker Change: The recently presented phase II data from <unk> 2002 in Asia can you discuss the.

Speaker Change: David any comments to share on 18 months versus a different follow up time.

Speaker Change: The data in the context of read through to the recently initiated phase III Halo study and any takeaways that you're applying to halo.

Speaker Change: Yeah. We felt 18 months was looking at their trials, we felt up to 18 months was the optimal time to really see the full benefit of the drug.

Speaker Change: Well thanks for the question and I think it's really important to step back in queue.

Speaker Change: It was not required by regulators, but it was it was really our own decision to do that.

Speaker Change: Considered what we've actually presented for 'twenty, two thus far if.

Speaker Change: If you take the 50 milligram doses from both the phase one and phase two studies. We now have we've reported on 12 of 15 patients who've achieved what we're considering a functional cure.

Speaker Change: The next question comes from Celgene Richter with Goldman Sachs. Please go ahead.

Celgene Richter: Hi, This is mark on for solving a first congrats on the quarter and thank you for taking our questions.

Speaker Change: That means patients following a single dose and no other therapy thereafter.

Speaker Change: The recently presented phase II data from until a 2002 in Asia can you discuss the.

Speaker Change: <unk> attacks that is unique in the space, It's a new category of response.

Speaker Change: The data in the context of read through to the recently initiated phase III Halo study and any takeaways that you're applying to halo.

Speaker Change: It is achieved.

Speaker Change: To our knowledge only with 22 of this class of drugs.

Speaker Change: Well thanks for the question and I think it's really important to step back in queue.

Speaker Change: We expect that similar outstanding results will come from our phase III trial. The study design is similar with the exception that we haven't even longer follow up period to see.

Speaker Change: What we've actually presented for 20 O two thus far.

Speaker Change: If you take the 50 milligram doses from both the phase one and phase two studies. We now have we've reported on 12 of 15 patients who've achieved what we're considering a functional cure.

Speaker Change: Further insights into how patients respond with even a longer observation period, what we've seen in our phase one study.

Speaker Change: That means patients following a single dose and no other therapy thereafter.

Speaker Change: Is that while many patients get to a functional cure fairly quickly.

Speaker Change: I have no attacks.

Speaker Change: Quickly there are some patients that reached not only with some additional time. So we expect that we'll have very favorable results in our phase III program and look forward to sharing that as we go forward.

Speaker Change: That is unique in the space, it's a new category of response.

Speaker Change: It is achieved.

Speaker Change: To our knowledge only with 22 of these class of drugs.

Speaker Change: We expect that similar outstanding results will come from our phase III trial. The study design is similar with the exception that we haven't even longer follow up period to see.

Speaker Change: Thank you next question. The next question comes from Myles Minter with William Blair. Please go ahead.

Speaker Change: Hi, Tim This is John on for Myles. Thanks, So much for taking our question.

Speaker Change: So for 31 I was just wondering if you could give us any idea of how many patients you are looking to dose before reporting initial data.

Speaker Change: What kind of targets are you looking for for CRM AAP levels in those lower dose cohorts.

Speaker Change: Thanks for the question.

Speaker Change: We've had a principle that we've applied since the outset with all of the clinical work that we've done here.

Speaker Change: Which is that we report data when it's meaningful consistent and interpretable and will.

Speaker Change: That same standard here, obviously, we're looking for a biomarker here, which is readily measured next to production of the native protein.

Speaker Change: <unk> type.

Speaker Change: And.

Speaker Change: We've said from the outset that our objective here is to normalize the levels of that protein and that will be the basis for determining the success of the project.

Speaker Change: Thanks next question. The next question comes from Joon Lee with <unk> Securities. Please go ahead.

Speaker Change: Hi, Good morning. This is maybe for June and thanks for taking my question.

Speaker Change: Given your great progress for in vivo programs that you have.

Speaker Change: Any color on your future plans for using June rising technology is really I. Appreciate it for example, do you plan to use it for in vivo or this is more for your ex vivo programs.

Speaker Change: Thanks for the question.

Speaker Change: Really goes to the heart of the strategy of the company, where it's a three pronged approach.

Speaker Change: We start with a platform that has a complete set of tools not only on the editing side, but also on the delivery side. So that as we look at any particular editing problem. We're in a position to choose what we think will be the best tool for the particular problem and we apply those tools in both the in vivo and DXP.

Speaker Change: Offsetting.

Speaker Change: We think that there are conditions for which gene writing.

Speaker Change: As well suited.

Speaker Change: Thats universally true.

Speaker Change: We think that there are certain instances, especially in the ex vivo setting where they said it is useful where one is going to multiplex and then of course as we've shown with our ongoing phase III programs archetypal CRISPR.

Speaker Change: <unk>.

Speaker Change: Simplified by 'twenty, one and 'twenty two.

Speaker Change: Profoundly successful results in terms of achieving the editing objectives that we're going after.

Speaker Change: No.

Speaker Change: In short we will look at.

Speaker Change: Particular programs.

Speaker Change: Editing that they need and applied achieve writing too that one of the places where we think it's well suited.

Speaker Change: And as an adjunct.

Speaker Change: Jumped to our Alpha one program and that would be the first place where I would expect to see it.

Speaker Change: Thank you.

Speaker Change: Our next question comes from Jay Olson with Oppenheimer. Please go ahead.

Speaker Change: Oh, Hey, congrats on all the progress and thank you for taking the question. How are you thinking about the ex U S opportunity and strategy for 20 O. Two are you interested in partnering the program ex U S. Thank you.

Speaker Change: Thanks for the question.

Speaker Change: Behind that is the assumption that there is a substantial commercial opportunity around the world certainly in the developed markets and we see that starting in the U S and going beyond the U S and to Europe.

Speaker Change: Europe.

Speaker Change: Perhaps beyond that are.

Speaker Change: Our current plans are to be in a position to launch the drug ourselves as we evaluate partnerships, we consider what they can bring to the table to extend our own reach.

Speaker Change: And as appropriate as we learn more about that we would share that strategy as we go forward.

Speaker Change: Okay.

Speaker Change: Great. Thank you so much.

Speaker Change: The next question comes from Brian Cheng with Jpmorgan. Please go ahead.

Speaker Change: Hi, Good morning, Thanks for taking my question. This morning. This is Sean on for Brian just speaking on the <unk> program. Just curious about your thoughts on the back of some of the RNA editing data from your peers, how do you view 3000 ones differentiation versus theirs.

Speaker Change: Thanks for the question.

Speaker Change: As we've said elsewhere, we think the key determinants of success for the pulmonary pathology of the disease will be achieving high Sn.

Speaker Change: Essentially normal levels of wild type protein.

Speaker Change: Thus far.

Speaker Change: We are the only company that we're aware of that's presented that in the setting the nonhuman primate that is what we're looking for in our phase one study to determine whether or not we achieve those same similar proteins in humans.

Speaker Change: Obviously, we'll watch the space there are competitive programs playing out.

Speaker Change: But it's very very early.

Speaker Change: We will see how successful people already been delivering their technologies and the performance of <unk>.

Speaker Change: Production of the normal protein overtime.

Speaker Change: Thank you the next.

Speaker Change: Our next question comes from Silvan <unk> with citizens JMP. Please go ahead.

Speaker Change: Hi, good morning, and congrats on the progress and thanks for taking my question.

Speaker Change: Just a quick one and I may have missed this but for magnitude too congrats on the <unk> IND.

Speaker Change: <unk>.

Speaker Change: But what.

Speaker Change: When do we plan the initiation in the U S. Here for this trial and what is the eventual split of patients enrolled in this trial.

Speaker Change: In.

Comparing U S versus ex U S. Thank you so much.

Speaker Change: Thanks for the question, we've tried to make it clear elsewhere that the study will be done outside the United States.

Speaker Change: It's there where one can readily conduct a placebo controlled trial.

Speaker Change: Standards of care otherwise for these patients are similar around the world.

Speaker Change: We've worked on developing this protocol with the food and drug administration in the United States.

Speaker Change: And they will.

Speaker Change: Except the program coming from patients that are studied outside the United States.

Speaker Change: Great. Thank you.

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

Hi, Good morning, Thank you for taking my question.

Speaker Change: For the HDD programs do you have any plans to expand this study beyond the New Zealand site and is it a reasonable base case that we would see data in 2025. Thank you.

Speaker Change: David you want to speak to.

Speaker Change: Any other sites Besides New Zealand.

Speaker Change: Yes, we will be having other sites and we'll put a mine Quinn Gulf Dot com is as they come up I should say it is.

Speaker Change: Possible that we'll have data.

Speaker Change: Reasonable to think we update on 2025.

Speaker Change: Yes.

Speaker Change: The next question comes from Andy Chien with Wolfe Research. Please go ahead.

Speaker Change: Alright, Brendon on for Andy I'm, sorry, no docs are excited about your a T T. Our therapy, but can you. Please compare the excitement relative to their excitement for stabilizers and silencers. So let's say you achieve similar efficacy on endpoints based on feedback now are docs much.

Speaker Change: We're likely to use gene editing compared to a sound answer for example.

Speaker Change: Any safety concerns about using gene editing in a very old population. Thank you.

Speaker Change: Davidson on the frontline talking to investigators.

Speaker Change: Can you speak to the enthusiasm for the investigators that we work with who by the way many of them have worked with silence is already so they are in a position to.

Speaker Change: Ill be thinking about both of those compounds.

Speaker Change: Yeah. Thanks, John I think you've heard our hypothesis for a number of years that deeper reductions in GTR will lead to better results.

Speaker Change: Our drug is also more rapid and getting down to low levels and silences.

Speaker Change: As well as getting to those deeper levels and is continuous so the the levels are stating continuously low instead of might widen happen. If you gave infusions of drugs.

Speaker Change: Periodically.

Speaker Change: So based on that that excitement about the low levels, we are achieving.

Speaker Change: Have heard a lot of excitement from the physician thinking this could be better than <unk>.

Speaker Change: It is something we.

Speaker Change: I wanted to prove in phase III, but that is.

That's what we hear from investigators and Thats why we think it's enrolling quite quite briskly there hasnt been.

Speaker Change: Any safety concerns raised in an elderly population, we've seen it well tolerated in all the patients including class III patients in some very sick patients and all of the patients were able to receive a full dose of the drug.

Speaker Change: As part of their therapy in the trial.

Maybe something to add is that.

Speaker Change: We now have over three years of follow up an earlier earliest dose patients and the excellent safety profile that we reported in the early days has continued.

Speaker Change: We think many of the questions that surrounded gene editing are being addressed.

Speaker Change: These programs are enrolled I think another thing to keep in mind with respect to patients who are older which typifies the wild type patient population.

Speaker Change: These patients live for a long time.

Speaker Change: Can look at the recently reported results.

Speaker Change: And see that there's high levels of survival years after that the patients have been dosed and I think that speaks.

Speaker Change: Importantly, too <unk>.

Speaker Change: All of these agents and what they can do for these patients the evolving care of them and ultimately a pharma co economic argument for treating patients like this who should derive the full benefit of the therapy.

Speaker Change: One other thing with respect to older patients.

Speaker Change: I'm going to think of GTR cardiomyopathy as a heritable disease in fact in most cases, it's a disease of the aging 90 plus percent of the patients who are suffering from the disease have wild type protein and you can see that in the phase III trials that have been reported.

Speaker Change: No.

Speaker Change: Unfortunately, we're making many more of these patients annually as the population ages.

Speaker Change: So it's not correct to think about it as a typical sort of genetic disease.

The next question comes from Whitney <unk> with Canaccord Genuity. Please go ahead.

Hi, good morning, and thanks for taking our question. This is John on for Whitney just trying to understand the rationale for the tubes are there one point neuropathy and given that the phase III will do bond ex U S. Any color you can provide on that just want to make sure we're not missing any nuance here. Thank you.

Speaker Change: Why do we have.

Speaker Change: Do the study outside the United States.

Speaker Change: Yeah. The reason is that when you plan a BLA in the United States. It's a good idea to get agreement with the FDA on the design of that study and that's what we've obtained with this IMD.

Speaker Change: <unk> agreed to the study Youre seeing presented today and.

Speaker Change: This will go forward to a BLA in the U S as well as around the world.

Speaker Change: This concludes our question and answer session I would like to turn the conference back over to Lina Li for any closing remarks.

Lina Li: Thank you drew and thanks, everyone for your questions. Today. We appreciate all of your continued support and look forward to connecting with everyone again after the AGM presentation on Saturday November 16th have a good day.

Speaker Change: The conference has concluded. Thank you for attending you may now disconnect your line.