Good afternoon. Welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I'm a SMID Cap biotech analyst . It is my great pleasure to introduce our next presenting company, Intellia. With us today, e have David Lebwohl, Chief Medical Officer. We also have Glenn Goddard, Chief Financial Officer. Glenn will give us a brief overview over the few slides.
Great. Thank you, Gena. I'll just start. We picked three slides from our corporate deck just to start us off, help level set, especially for people that may be newer to Intellia. This first slide I think is an important one. It's really how we've built the company and really focuses the company strategy in one picture here. One at its core based platform that's based on a set of novel tools that we've pulled together, and it's on delivery tools. From this foundation, we're building an emerging pipeline. The way to think of that pipeline really is in two areas of focus. One being in vivo applications of CRISPR and CRISPR related tools. The way to think about that is really using CRISPR as the therapy.
To think about it at a higher level is we're trying to fix broken genes and applying this in the genetic disease space. On the flip side of this slide, we talk about ex vivo and using CRISPR to create the therapy. What we think about here is really using cells and rewiring them to give them different functionality to and use them in the oncology and autoimmune space. As I click ahead to this next slide, really this summarizes the last two years, some of the key important milestones that the company has achieved. I think one of the things we're really proud about is we're really the first and only company to demonstrate successful systemic CRISPR-based genome editing in humans. To date, we've dosed over 50 patients.
Now we've shown clinical data from three programs successfully, we're well-positioned to start the first ever CRISPR-based pivotal trial. If you look to the pipeline, we have over 10 programs that are moving forward. We've done six collaborations to date. The underpinning of this is our deep platform based on CRISPR. If I click ahead, now if you think about where the company's focused for the next two years, only three key areas here. First and foremost is we're gonna be laser-focused on starting global pivotal trials for both our TTR and HAE programs t hat's priority one. Second is really bringing new programs forward that leverage our gene insertion capabilities and our genetic technology. We're very excited to be moving these programs forward as well.
Behind this, we're gonna continue to bring forward, some of these new gene editing capabilities we've been talking about in delivery modalities into our pipeline. Stay tuned for that. That's a really, a good snapshot of where the company's focused as we look forward for the next two years. That's our overview, Gena. I'll turn it back over to you to start the chat.
Sure. Sounds good. I think that you recently achieved very important milestone with clear IND in the US. Actually, that's the first ever IND that cleared. Can you share some feedback on the safety profile that FDA was looking for, and what is the difference between CTA and IND?
Okay. Well, thank you for that. The what the Europeans want in a CTA and what the U.S., they want and the FDA wants in IND, actually it's not very different. They're pretty close, but each authority has individual reviewers who have their own questions, ideas about things, and we obviously prepare to be able to answer those. The achievement in the IND was based, most importantly, you know, INDs usually go in for first in human studies. We're coming in for phase II. What's important there is they're gonna look very carefully as they do for phase I at how you manufacture the drugs. That's very key for them. In the case of in vivo gene editing, a big question is about, have you seen, is there off-target editing?
How do you test for off-target editing? We think, we do think we set the standard there. We've talked, we've given talks to the FDA to say how we do that, and of course, the clearing of the IND is some validation of that at that point. They also ask for early non-clinical studies. How do you, they're interested in potential for germline editing, those type of things. In our case, what was great is we did have that safety data, and the drug looks quite good in terms of tolerability at the three doses we've tested. They also had to agree to the phase two design. Part of this is saying you're studying two doses, 25 and 50, which looked very good in the first part of the study with a placebo arm, and that was again supported, going forward in the IND.
That's very helpful. You know, the kind of thinking because now you have a initial experience with the IND clearance, and how would that help you, now you have also very important IND clearance for the global phase III study. How much luck do you have and how much extra confidence you gain by clearing this IND?
There are a number of things this helps us with the TTR IND. One of those fundamental things we talked about, how do you manufacture the drug? How do you test for off-target editing? How do you do the safety studies, pre-clinical studies? Of course, the safety that we saw in HAE with the [LFT] is really the very similar safety that we did see in TTR and had expected to see in TTR. They support each other in terms of.
Of clinical safety. There are differences in these INDs. In the case of the TTR IND, we are asking to do a phase II study. That's a bigger ask of the FDA. This is the study that will lead us to the BLA, so they will be very careful in terms of the design of that study. You also have to do more controls for your drug manufacturing as you go into phase III, so that's important. On the positive side, those are the, you know, increased hurdles. On the positive side, we have more than 40 patients treated. We'll be bringing them data on that set of patients. They have, again, very good confidence in knowing what our drug does in these patients.
David, you mentioned that you will need a more controlled form of manufacturing. Maybe can you elaborate a little bit more what kind of more control compared to, say, the HAE RD forms?
The main thing, as you go into phase III, your drug has to basically be the same drug that you expect to see in the commercial setting. It really should be the process that gets you there. The, you know, parts of that are always complicated, but in this case, it's been a fairly straightforward scaling up to get there. We do think we've addressed the questions they've asked about in the pre-IND meeting.
Okay. Very good. The timing for submission is still on track mid 2023?
That's right. From mid 2023 is the filing.
Okay. What is your definition of mid 2023? Every company has a different definition.
A definition.
Yeah. To be clear, mid this year could be any time in Q2 of 2023.
Okay. 2 Q2, 2023. Okay. Good. Will you announce or will you be similar, you announce submission, or will you announce when it's FDA give you feedback?
Yeah. The plan would be to announce once we get feedback from subject. Yeah.
Basically once a quarter.
One month. You hear from them.
Oh, yeah. Sorry. It's on you.
Yeah. Hopefully two months don't make that a whole. We should hope not.
Yeah. That's right. Yeah. Okay. Very helpful. Now switch gear to the we report. Regarding, you know, this one which will be coming later this year. Maybe first like, you know, would that be at the medical conference?
Yeah. Yeah, the plan would be to have medical conference. I think, you know, the first data. Sh owed the events go away completely. We're very happy with that. Patients treated. We haven't shown yet data on events at 50 mg. Actually bridged by the 25 mg and the 75 mg. We know what we anticipate there. The other thing is we'll have longer follow-up on the patients as well. It'll give you a pretty good idea of what's gonna happen in phase II, 'cause we'll have the whole spectrum of doses.
Given you've already issued 25 mg and the 75 mg, I show actually if we look at the attack rate reduction starting from week five, actually these two are very comparable, 89% reduction. Would that be, you know, kind of reasonable to think in the particular range, maybe similar range?
Yeah. We would think it's going to be similar to the other the main difference between even the 25 mg, the 50 mg and 75 mg are very similar in terms of reducing prekallikrein. The reason we chose the 50 mg for phase II is a lower dose that gets basically the same effect as 75 mg. 25 mg actually had a more uneven reduction of prekallikrein. Again, we wanted to test the lower dose and have these two doses to compare. If attacks went away, both, it's hard to say one is really better than the other at this point.
What additional data could help you understand which dose will be the best dose with the longer follow-up? Like, should we expecting to because the post first two doses, you do see HAE, like most of them already. The last follow-up is already attack free. Like, what would be the best data point to help you understand this is the right dose?
There are a couple of things. One, of course, is always safety. Safety first. At both doses are safe. So far, they're both extremely safe in terms of side effects. The only thing that seems to be related to the allergy are infusion-related reactions. Next big point is how consistent is the effect on the pharmacodynamic endpoint, which is both prekallikrein protein, prekallikrein activity. It was more consistent at 50 in the initial part of the study, but we do need more patients to really confirm that. Then, of course, the attacks over time. Are there any breakthrough attacks at one or the other dose? What can we say about that?
Okay, good. You know, the other part is, so on the clear, U.S. RMD clear, and then this is ex-U.S., we already start enrolling patients. Maybe a little bit more color on the U.S. sites, how many active sites? You know, we are giving, we have pretty good standard of care. You know, give us a little bit color on how you see demand there, you know, the enrollment speed, if you could.
Yeah. In terms of starting up in the U.S., we did just get the IND. You really need that at most sites in order to activate sites. The activations are in process, and again, not saying yet exactly when that will happen. Also, we are screening outside the U.S. The trial from what we're hearing from the investigators will enroll quite efficiently.
The second question was, yeah. I'm trying to remember, what was the second question again?
I think the speed of the enrollment.
Yeah. Yes. What we think is, you know, based on what investigators are telling us.
Mm.
it should be quite brisk.
Okay. I mean, if we look at phase II study design only have 10 patients in 25. The other one also 10 patients, placebo five patients. It's a relatively small number of patients. Like how quick do you think you can complete enrollment? Now you have the U.S. on board now.
Yeah. We want to go as quickly as possible. I guess one thing, we did show is we want to be in pivotal studies by next year. I guess that's.
Okay.
during the next year, you know, in, by, the next two years. That gives you an idea. We want to get that result and launch a good program in that period.
Okay.
Yeah.
Which means we should see the data sometime this year for you to start next year.
Not necessarily. Can't say exactly, but-
Okay.
The one thing I'd say, you know, you're saying it's a small trial. Pivotal trials in this area can be 80 patients.
Yeah.
25 patients may even see a significant difference from the arms because the effect size is so large. The patients who aren't treated, you know, will continue to have attacks. As you can see, if we go to zero attacks in the active arms, you can see quite a good result.
Okay. Any restriction regarding what percentage of patient has to be from U.S. for this study?
No. It, you know, we want to enroll it efficiently to get to the pivotal study. Of course, when we get to pivotal, we want to enroll. I know you did ask about patients in the U.S.
Mm.
There's a lot of interest. If you think about it.
Mm.
patients in the U.S. might be taking Tacrolimus. They have to go, most commonly, they have to go in periodically to the doctor. They can have breakthrough attacks.
Mm.
The levels, obviously, can change. Miss a dose, particularly.
Mm.
The idea that a single dose may treat them for life, that they may need no more, may have no more breakthroughs if it goes very well. That, that is definitely driving a lot of interest, not, you know, not only overseas, but also in the U.S.
Good. Another question is a naive patient versus patient already on prophy. Like, any thoughts, like what kind of patient population?
Yeah.
you'll be selecting?
Yeah. The patients like all these pivotal trials are done with patients who've not on prophylactics. Some patients may withdraw it because they want to be on the trial.
Mm.
During the, you know, the observation that they can take rescue drugs so that, you know, it's not not threatening to them to be able to take off the prophylaxis in that period. Then as soon as possible, we'll get them randomized in the trial.
Okay. Basically, prophy patient, you know, wash out and then taking it.
Wash out.
Okay, good.
Yeah.
The baseline attack rate, any thoughts like?
It's pretty much a standard that patients have at least one attack a month is the most standard. We haven't said exactly pivotal design. We do have to discuss it with health authorities.
Mm.
Something like the existing credits will be there.
Okay, good. Very good. I think I will switch gear to TTR programs. Some, you know, additional steps we've kind of discussed. You know, for you to submit, we only have maybe a few more months.
Right.
To submit. Like, what are the remaining steps you need to complete?
This program is, along with the Regeneron hemophilia program, are our first two insertion programs. Here, instead of knocking out the gene, we're putting in a new gene into the targeted locus. It is a little more complex. The LNP we feel very confident about, of course.
Mm-hmm.
What we've done with the other programs that this will be able to target the albumin site in this case. We're using albumin because of the very high levels.
Sorry. Just, maybe I was confused. ATTR.
Oh.
Yeah.
Oh, ATTR. Sorry.
Yeah.
I was thinking AATD.
Sorry. Okay. We were also asking that.
We know. All right.
That program.
Oh, the next steps there.
Yeah. Yeah.
In this case, you know, we said we've treated all the patients. You know, we're treating part two by the end of the year.
Mm.
We talked about that with cardiomyopathy. We are, you know, the other steps we've talked about are talking about putting together the documents about the drug manufacturing is certainly very important.
Mm-hmm.
Summarizing the safety from the, from the new patients as well. Putting in a phase three trial. We're working with pretty much every leading investigator in this area around the world to help inform how we're designing the trial. That's all, you know, that's all coming together. It takes a while to assemble that, and then it'll be the middle of the year.
mainly is assembly existing data.
Yeah.
You do not need to do more, say, some assay or anything.
Yeah. Yeah, at this point, we are putting it together.
Okay. That's very good. Now the phase I additional data in 2023, maybe, you know, again, similar like timing of data update and also, venue or format of the data update?
Yeah. We like to be at a medical meeting.
Mm-hmm.
We haven't, you know, we haven't said exactly what meeting that would be, but we always do announce it before we get there.
Mm.
Of course, we'll have more follow-up on the existing patients who are treated 55 mg, which we predict will be the phase III dose. The other thing, because it's been about a year, we started information on some the cardiac functional things. One thing we're very interested in is cardiac MRI is a very good way of gauging what's happening to the actual amyloid in the heart. That, you know, what we would, that will be a very good measure of beyond the TTR levels as well.
Okay. The NIS score, will you also be able to share that?
The,
The NIS score.
Oh, NIS score.
Yeah.
Yeah, I'm not sure. You know, That, of course, you have to have enough data to put together and we'll see as we get to the time. The most main focus, most important focus to most people. For polyneuropathy, we are again planning, you know, designing a pivotal study now, but our priority has been cardiomyopathy, and then polyneuropathy will come after.
Okay. I think that makes sense. It's a much larger problem.
Yeah.
Yeah. Yeah. The cardiomyopathy, I can remember in the past, will we also see the additional safety because you did, I think, complete the cohort, lost track cohort two?
Yeah, part two.
Yeah, yeah, part two. Yeah.
Yeah. That's the patients of 55, and that will be full data on those patients.
Okay. safety and then
Yeah.
The efficacy and the cardio measurement.
Yeah.
Okay. Thank you.
Most patients will be early for the cardio measurement, patients, you know, the end of the year, but some of the earlier patients will have some information.
Okay. Now going back to study design, that's not that long distance. That would be like end of this year.
Yeah.
updating the thoughts. Really, you know, your updated thoughts on what will be the best trial design that minimize the development trajectory that you need to?
Yeah. We think there are a couple important features. It, you know, it is gonna have to be a larger trial like HELIOS-B.
Um, and I think-
Even maybe I wanted to ask you because Ionis has a 1,400 patient. Like, I think you want HELIOS-B like or the Ionis?
I think if you have a good treatment effect, you know, you need a smaller trial. We do anticipate that we wouldn't need that large a trial to show the treatment effect. Of course, the huge thing we have in design is we will see the results from those other trials before we unblind our trial. As you know, AstraZeneca enlarged their trial for reasons that are completely explained. You know, we would also have the opportunity to enlarge the trial and make other modifications to the analysis based on what we see. In terms of other design features, we think a lot of the patients will be on supplements. It's being very widely used in the world. There still are places where the patients would not be treated with supplements.
We're used to also similar like, HELIOS-B allows the patient to supplement?
For sure, yeah.
Yeah. Wouldn't that cause some, you know, heterogeneity of the patient population? Why not allow everyone to supplement?
They could be allowed, but that's not available to some people. That's part of it. Parts of the world where they can't get access to the supplements.
Okay.
We do think a majority of patients will be on it, given the use of it around the world now.
Mm-hmm. Okay. The control arm, you would be thinking a two plus or like, would similar like HELIOS-B study?
Yeah, like HELIOS-B. It'll be a placebo like HELIOS-B.
Okay.
Because there's no TTR lowering agent that's approved, that's the appropriate.
Mm-hmm. Okay. This is very helpful. Now we switch to ATTR. I know you started. Let me go back.
To the answer again. ATTR is our first insertion program along with the hemophilia program at Regeneron. What we've seen preclinically is that the normal levels of alpha-1 antitrypsin in non-human primates, which is something that has not been achieved with any other therapy to get to normal wild type alpha-1 antitrypsin. The, the difference from this from the other studies is, you know, the likelihood of success is much higher because we have been successful with the TTR program and the HAE program. Because we know that the LNP that we use is almost identical. It's modular, but it hits, instead of hitting TTR or prekallikrein, now we're hitting the albumin locus. The idea is there, that's the best place to put the new gene because you get very high levels of expression. In this case, gene is contributed by a promoterless AAV. Should be relatively safe compared to other types of AAV at relatively low doses to take. That AAV contributes the alpha-1 antitrypsin that goes into the albumin locus.
Mm-hmm. Basically very similar to the [HEMA] and [HEMB], right?
Thanks.
Insertion to the albumin, and I would assume the, after the first control, right?
Yeah.
Yeah.
After, yeah, that's right.
Yeah. Okay, good. Then, you know, oh, by the way, what is the status of the [HEMA] program?
Yeah.
I know it's a partner program.
Yeah, the partner. Yeah. We actually let Regeneron talk about that, basically.
Regeneron, just to be clear. Regeneron is the lead party, so they're the ones who will speak to it. They have that program is lining up well with NTLA-3001. Those programs are going well.
Hemophilia B lining up, and then hemophilia A is coming after that.
Yeah. Okay. Going back to ATTR, the R&D now slightly differently, but we do have insertions slightly differently mechanistically.
Mm-hmm.
What do you think about the R&D package, additional data pack you need to include so that you can have also one shot for here?
Yeah. You know, the biggest new piece of this is the AAV itself. Of course, the requirements of that. Now, that's been pretty well worked out because as you know, a lot of gene therapy companies, we know what they need. As I said, it's somewhat safer than a traditional gene therapy AAV. Of course, they'll be interested in all the same questions. How have you manufactured this? What are your preclinical studies show in terms of safety?
Of course, the expression is very good, as I say, so that I don't think there'll be any questions about the possibility of benefiting patients because you're getting alpha-1 expressed in those patients. And of course, the trial design itself, you know, we're interested in. A big part of that is dose selection. Now you have two drugs, two drugs, but two elements. You have the LNP and the AAV, so it's a little more complex, and we're doing a lot of modeling work to pick the right doses to go to.
Will you, the two different, I assume both will be IV infusion? Will you, do the same time, or you have like a spacing out one day apart? Any thoughts there?
Presumably there'd be some spacing that we're, you know, we will be justifying again in the IND of why we do that spacing.
Okay.
Just on the basic idea, you probably want the AAV to be there when the gene is targeted so that...
Yes.
It's ready to contribute.
Yeah.
Yeah.
Okay. Okay. I see. Since you are inserting into albumin promoters, leverage albumin promoter, right? Any extra safety package you need to present to the FDA?
I think that it's important that you don't wanna lower albumin. If you.
Yeah.
Let's say you insert it into every gene, that would be a problem. It hasn't in general, you know, we don't think you're getting to a high percentage, but you don't need a high percentage 'cause the albumin promoter is so strong that you just need a small proportion. Our findings would be what is the albumin in the patients in the animals pre-clinically? They'll be interested in that for sure.
Okay. Actually, is there any like upper threshold the FDA do not want you to go above?
I think people feel the higher you have for what interest, the better.
Yeah.
No one thinks that I haven't heard anyone problem with going to higher levels.
Like in terms of, insertion.
Oh.
Like albumin expression. Yeah.
Yeah. I think they'd be very interested in what happens to albumin patients, and that would be an important feature. The animals first and then the patients.
Okay. I kind of very expecting more ahead. I think that insertion level is like less than 1%.
Yeah.
Okay.
Very different.
Yeah. Well, I think we are running out of time.
Okay.
Thank you very much. A lot of update, and then we are looking forward to important, you know, additional milestone later this year.
Yeah. Great.
Thank you.