Operator: And the next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Excuse me, Salveen at Goldman Sachs, your line is open. Is it muted accidentally on your side?
Unidentified Analyst : Can you hear me?
Operator: Go ahead. Thank you.
Unidentified Analyst : Hi. Sorry, this is Olivia on for Salveen. Thanks so much for taking our question. Just another on 2001. Could you just speak to your comfortability around the powering for the MAGNITUDE trial and when you expect to complete enrollment? Thanks so much.
John Leonard: David, you want to address that.
David Lebwohl: Sure, so we are very confident in the design. Recall that we’ve used an events based study rather than harping the follow-up on patients. So the advantage of this, of course, is that you would not need to extend the time of the study based on perhaps slower event rates as you predict. But given that we did make a very conservative estimate both on our powering and predicted event rate. So again, we’re confident in what we have with the design with a larger study than HELIOS-B at 750 patients. The completion of enrollment we have said is going to be in the — yeah, it would be looking at some of the other studies to get a sense and you’ve seen that these studies enrolled very quickly. And so that would give you a good idea when we do expect to complete enrollment.
Unidentified Analyst : Thanks so much.
Operator: The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.
Unidentified Analyst : Good morning. This is Rai on for Debjit. Do you see opportunity for 2001 differentiation by potentially enriching the MAGNITUDE trial with NYHA Class 3 subjects, or other patient demographics that capture sicker population relative to contemporary ATTR-CM trials?
John Leonard: David, do you want to speak to the mix of patients. We’ve allowed in patients who are — have more advanced disease, what does that do for us?
David Lebwohl: We do allow, of course, Class 3 patients. An important feature of what we looked for is patients who are somewhat sicker than the other studies. And the way we did this is to have the baseline proBNP be greater than 1000 and to not have an upper limit on the proBNP. This could differentiate us in a few ways. First, we did this because the — by the events occurring more rapidly, the trial will be completed more rapidly. In addition, we do think these sicker patients are the one most likely to benefit from TTR reduction. If you’re — if you have a very healthy patient, they won’t have events in either arm of the trial, and they really won’t contribute to what we learned about the trial. So we do — we do think that by choosing these patients, we will be able to differentiate our treatment of getting to lower TTRs and the other treatments in this study.
Unidentified Analyst : Got it, thank you.
Operator: The next question comes from William Pickering with Bernstein. Please go ahead.
William Pickering: Hi, thanks for taking my question. In AATD, what dose level of AAV was used in your NHP studies and how were the human dose equivalent compared to what we see from traditional AAV gene therapies that aren’t integrating into the genome? And how much margin for error do you have on not lowering albumin in terms of the insertion efficiency that you’re expecting versus the levels that would be required to make a meaningful dent in albumin levels? Thank you.
John Leonard: We’re not speaking to the precise dose of AAV but it’s lower than what’s used for standard gene therapy. Laura, maybe you could say a word about the strength of the albumin promoter and why just a few integrants are necessary to get to the levels we need.
Laura Sepp-Lorenzino: Yes. So, albumin promoter is the strongest promoter for liver, so you just need few percentage of cells to have been a productive insertion to achieve normal levels. Here we’re looking at 22 micromolar as an average rate. So, the preclinical data of course we did metrics of LNPs and AAV keeping the goal as John just said, to ensure that the AAV dose is slow with the need to hit all the cells in the liver. And that gives us safety. We feel very good about the margin. Oh, and with regards to albumin, we do not see significant decreases in albumin, right, because you’re only editing in a few cells. So albumin expression remains constant and that we’ve seen in preclinical models, and that was further evaluated in our GLP tox studies.
William Pickering: Thank you.
Operator: The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead.
Rick Bienkowski: Hey, good morning, everyone. Thanks for taking the questions. The pivotal study in HAE, given the timelines for the potential 2026 BLA filings, I wanted to ask about the degree of confidence and being able to use a six-month primary endpoint in the pivotal study just given gene editing mechanism is so different from the competitors here? And also in the Phase 1 data, there was the initial 16-week period after dosing where some patients experienced breakthrough attacks. I was wondering if this phenomenon could be accounted for in the pivotal trial design in any way?
John Leonard: David do you want to speak to six months endpoint, I mean, obviously, you’ve been on the front line talking to regulators around the world. Do you think that there’ll be the need to extend beyond these two standard sorts of approaches?
David Lebwohl: Yeah, what we believe is that the six month endpoint which has been standard in these studies will be the same standard that we apply to this study. In terms of longer follow-up, of course we will have Phase 1 and Phase 2 patients with longer follow-up when we filed the DLA and as well as a very extensive safety database from our other knock out program with TTR. So we do feel very confident that the safety database we’re bringing will be satisfying what the regulators want. Of course for all gene therapies we will continue to follow the patients for the standard 15-year period. In terms of the breakthrough attacks, we are looking at how to account for this in the pivotal study. We’re not talking about the exact design.
You have to recall those patients were only the patients who had very unusual number of attacks, up to 15 attacks a month, as you recall. So that this — we don’t expect — that’s an unusual patient kind of patient who was waiting for the Phase 1 study. Most of the patients in the study will be more like the other patients where the attacks were pretty much gone after the infusion.
John Leonard: Rick, I appreciate your noting the BLA in 2026. It is one of our key strategic objectives for the company in the next two to three years. And we’re very excited about being in a position to take what we think will be the very first In Vivo CRISPR based approach to approval and go into what we think is a marketplace that we can be extremely successful in.
Rick Bienkowski: Alright, appreciate the color. Thank you.
Operator: The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Yanan Zhu: Great. Thanks for taking our questions. So just wondering, a very quick one on MAGNITUDE, what is the percentage of tafamidis patient you target in a trial? And also wondering if you could talk a little bit about your DNA writing technology, I think this is the first time we hear about a program since you acquired the technology in 2022, so wondering if, for example, is there a correction template and whether it is RNA or DNA format? Thank you.
John Leonard: Maybe I can say a word about the writing — DNA writing approach. And David will address how we think about tafamidis and the MAGNITUDE study. The way we think about gene editing in general is capabilities. By that I mean, introducing the particular type of change that one is interested in introducing into the genome for whatever therapeutic purpose. There’s different ways to introduce those changes. When we think about gene writing tests, that’s a category that brings with it a variety of approaches to introduce a string of nucleotides. As you commented, we acquired work that was a complimentary to the work that we’re doing a couple of years ago. And we’re excited with what that brings to us to add to the work that we’re already doing.
And at the right time and the right place we will talk about exactly what we’re doing and how it fits into our pipelines. But I think that it’s just important to note at this point, that we’re making excellent progress and doing everything that we want the technology to do. David you want to say a word about the tafamidis.
David Lebwohl: For tafamidis we expect about half the patients to be treated with tafamidis. And this is similar to what’s been seen in the pivotal studies that have been reported so far as well.
Yanan Zhu: Great, thanks for the answers.
Operator: The next question comes from Steve Seedhouse with Raymond James. Please go ahead.
Unidentified Analyst : Hi, good morning. This is Timor on for Steve Seedhouse. So we have a question on AATD. Historically, it’s been difficult to show improvement in lung function with augmentation therapies and other therapies on endpoints such as FTD1 [ph] or pulmonary exacerbations. And even more advanced augmentation therapies haven’t attempted to show this improvement. So how do you think about improvement in lung function, do you expect regulators to require you to show an improvement?
John Leonard: David, do you want to take that.
David Lebwohl: Yeah, the regulatory standard hasn’t been set here. There have been some reports publicly that the FDA may accept having normal levels of Alpha 1 antitrypsin could be a way to move forward, of course with some associated clinical findings, but not that square — certainly a definitive improvement. And we do think because our program can get to normal levels, really the only gene editing program that’s shown us so far, that this may be something that the regulators will work with us on and have given us a way forward to an approval mostly based on the high levels that we’ll be achieving.
Unidentified Analyst : Thank you.
Operator: The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Jay Olson: Well, hey, thanks for providing the update and congrats on the recent collaboration with ReCode in cystic fibrosis. Can you just talk about some of the features of the LNP platform that you found attractive and what is the root of the administration and did the collaboration only focused on cystic fibrosis or could you potentially leverage the collaboration to study additional targets and diseases? Thank you.
John Leonard: Laura, you want to take that.
Laura Sepp-Lorenzino: Yeah, sure. So ReCode has been pioneering a new class of lipid nanoparticles that are targeted to different organs. These are the short levels. They have, we were quite interested in what they were doing in the lungs. And as you may know, they’re already in the clinic to inhale, LNP mRNA for PCD and cystic fibrosis. Actually, I think they dosed the first patient with an mRNA yesterday. So with these LNP that goes to lung for which they already have preclinical and clinical data, and the manufacturing and the route of administration of inhalation, they have demonstrated that they can get to not only the mature cells, but also the target cells that you need to edit to have long lasting benefit if you’re looking after a CFTR correction.
So when we’re looking at partnerships, we’re looking to marry technologies. We have a strong gene editing technology that allows us to target specific mutations, and they bring in validated delivery modalities. So I think it’s a great partnership and we’re looking forward to make quick progress.
Operator: The next question comes from Silvan Tuerkcan with JMP Securities. Please go ahead.
Silvan Tuerkcan: Yeah, good morning. Congrats on the quarter and congrats on the progress. And thanks for taking my question. Just a quick one on the HAE program. What are some of the considerations that you’re thinking about selecting the dose for the Phase 3 and what can we see in the Phase 2 data bit later this year to give us confidence in that dose selection? And then regarding the Phase 3 design overall, is there any impact or any information that we’ll get from the Phase 3 Oasis HAE study from — presented, you know, mid-year that will help us also like in the design, I think about the design of the Phase 3 trials? Yeah, thank you.
John Leonard: David, how do you choose your dose for Phase 3.
David Lebwohl: So recall that we’ve completed the enrollment to a Phase 2, in which the patients, there are 10 patients on 25 milligrams, 10 patients on 50 milligrams, and five patients on placebo. So we have a very good setting in which to evaluate those two doses. We chose those two doses because of the dose escalation phase. As you recall, all patients basically achieved no events after the infusion except a single event in one patient a year after treatment, which was related to a sports injury. So with the Phase 2 we will have a very extensive database of these two doses. The things we’ll be looking at, of course, is the clinical findings, the event rate, but also the consistency of the pharmacodynamic effect we’ll be looking at as part of this.
There was more variability at the lower dose. So on first principles, we would tend to think that the 50 dose is going to be better, but we want to look at all the data and make a decision about the Phase 3, and it will be a very robust decision based on this Phase 2 study.
Operator: The next question comes from David Lebowitz with Citi. Please go ahead.
David Lebowitz: Thank you for taking my question. A competitor has a switch study for its HAE trial and I’m just curious as to whether there is a similar type of study that would be needed or what that would look like for a gene editing product?
John Leonard: You want to speak to that.
David Lebwohl: We haven’t talked about doing a switch study. In the pivotal studies what usually happens is that you withdraw from any kind of prophylactic therapy. We have seen in our study patients withdrawing from Lenzilumab [ph] as well as other prophylactic therapies. And we do think that will be of interest to patients when this is an approved drug therapy to get off the therapies that they have to take repeatedly and go on to a onetime therapy. So we haven’t yet guided to there being a switch therapy, but this is something obviously that would be considered a switch study.
David Lebowitz: Thanks for taking my question.
Operator: The next question comes from Jack Allen with Baird. Please go ahead.
Jack Allen: Great, thanks for taking my question. And congratulations on the progress. I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients in MAGNITUDE as compared to HELIOS-B and how do you expect positive results from HELIOS-B could affect enrollment in MAGNITUDE, meaning MAGNITUDE will be a placebo controlled study?
