David Lebwohl : Sort of discussed already, the way we think about it is that the lower the amount of this precursor protein of the abnormal protein, the better the effect on the disease. And in fact, if the protein gets low enough, then what we expect, not only that you don’t start, don’t accumulating amyloid, but you actually might see the reduction of amyloid that the body will remove the amyloid from organs. So our goal is to get the lowest absolute TTR levels. We’ve talked about that in some of our recent work. In fact, at some people, at some point people may asking, what is your TTR number that’s going to be the important thing moving forward. What happens with tafamidis, if you do get the levels low enough, then tafamidis could be valuable still because the bit of remaining abnormal protein could be stabilized.
You go from what is a very low amount already with our drug to make it even somewhat better perhaps with the tafamidis. It may be a valuable interaction, it might be a synergistic interaction as you get to these very low levels.
Laura Sepp-Lorenzino : With regards to the question on the gene insertion and how do you maintain therapeutic levels as part of the preclinical development package involves doing a matrix of dose of how much LNP and how much insertion template, right? And you clearly and deeply characterize what’s the range of insertion that results in therapeutic protein production. And that data is then taken into account all scaling for humans, right? That’s part of your clinical development plan. In the clinic, there is going to be a very purposeful and safe way of dose escalating to understand what’s the level of expression and how does that translate across multiple patients on the cohort. So, reminding that factor — is being driven by Regeneron, so they’re already approved to move into the clinic.
And we’re expecting, we’re going to be seeing data, clinical data, in due time, which not only is important for that program, but is a validation of the insertion platform that will translate to 31 and a number of other diseases for which insertion is the most appropriate gene editing modality.
Unidentified Analyst: Part of the question was how to maintain levels. Maybe you could say a word about the stability that we expect.
Laura Sepp-Lorenzino: And for maintenance, right? We have shown now for factor nine for alpha-1 and other inserts that, once that’s stable inserted into the genome, you see very, very stable insertion. This is a key difference from traditional gene therapy where you have an epitone where over time that epitone could be silenced or can be lost just by the proliferation of the liver cells over time. So we expect that once you achieve those stable levels, those are going to be persistent and well controlled.
Operator: The next question comes from Mary Kate Davis with Bank of America.
Mary Kate Davis : I guess looking at your earlier stage pipeline with your recent collaboration with recode, could you talk about the opportunity in potential market with gene editing medicine and cystic fibrosis, and maybe also the opportunity of utilizing your DNA writing technology to address this indication?
John Leonard : I’ll start. Why we’re excited about cystic fibrosis and maybe Laura can talk about some of the technical things that we believe we can address successfully with our approach. As I think as well known, there’s many people who suffer from cystic fibrosis in the United States and around the world, and therapies that currently addressed are chronically administered. There’s no doubt that that’s represented in advance for patients relative to where they were some years ago, but the fact remains, this is chronic therapy and many of these patients continue to progress. There’s a set of patients for whom no therapy is available, and as exciting as some of the advances are, that they’re just irrelevant to a large subset of these patients.
This is a very large market as we’ve seen with other companies, and it’s something that we think we can make some very, very significant contributions to it. Maybe, Laura, you can say a word about how we can address that and our work with [Indiscernible].
Laura Sepp-Lorenzino : Yes. So, as John was saying, right, we believe that cystic fibrosis is there is still significant unmet medical need, not only the people who don’t respond to carbon therapies, but there are patients who don’t tolerate them. Important among those patients is what’s called the Class 1 that they don’t make CFTR protein. So we believe that that’s a perfect place for us to start by combining our DNA writing efforts with ReCodes, LNP, we were encouraged to see the LNP development by ReCode and particularly they’re in the clinic, we inhale LNP for two indications, one being CFTR. They have really robust preclinical data demonstrating that they can get to the cells that we need to edit to have persistent long-term CFTR correction. So we’re very enthusiastic about the collaboration and really pushing experiments to move as fast as we can. Great team on both sides working together.
John Leonard : I think the ReCode work is a good example of our approach to partnerships in general. We look for leaders in the space, people that share our values and approaches to patients. And those are the partnerships that we think are going to yield important new drugs. And we look forward to the five areas that we’ve talked about in our comments as we now progress outside the liver.
Operator: The next question comes from Rick Bienkowski with Cantor.
Rick Bienkowski : Congrats on all the progress and thanks for taking the questions. So for 2001 in TTR I had a follow up from Lucus earlier question magnitude I hoping here your thoughts on how important it is for 2001 to show a strong treatment benefit on top of tafamidis and what the potential commercial implications would be for showing different treatment effects in the patient’s on baseline tafamidis versus those not on treatment.
John Leonard : David, do you want to address, the benefit and importance thereof?
David Lebwohl : And so, I think what we believe is that the drug can be 2001 can be better than tafamidis as a single agent. We also believe that will be a benefit on top of tafamidis. Of course, that’s still to be proven. What we are hearing from investigators and physicians is that they’re looking for better drugs for this disease. Patients continue to progress on tafamidis virtually all the patients as best we can understand from investigators and from the literature. So we do think there is a role for a single agent that is better than what tafamidis is doing. This could be seen in the patients who are obviously are not receiving tafamidis in the study. So this will be an important analysis as part of our work.
John Leonard : I think it’s important to state that nobody is satisfied with tafamidis. I mean, patients all progress on that drug. The disease remains a mortal illness and investigators and patients know that. And what we think will prevail in the marketplace is drugs that offer the very best outcomes to patients. And that’s the approach we’ve taken from the beginning of the development program. We’re excited with the data we’ve seen thus far, which we’ve been sharing, and we expect to show that at the end of our Phase 3 trial that we represent a significant advance over what is currently the state of treatment, whether used in combination or alone. And that’s going to be a real advance for the field.
Rick Bienkowski : I just had a quick follow-up on alpha-1. Since there’s two moving parts here, the LNP and the AVV was hoping you could just comment on how you’re thinking about the dose escalation. Would you be able to escalate both components in tandem or would you have to maybe do an extended dose escalation to control for those two different delivery vehicles?
John Leonard : I’ll turn to David, but just to set the table, we do a lot of free clinical work to try to address as many of the variables as possible before ever entering into the clinic. So I don’t want anybody to think that we go in with a complete unknown. Just as our work with 2001 and 2002 where we shared earlier our modelling was essentially dead on in terms of what we saw in the clinic. We expect that many of the insights we’ve learned from the preclinical work will apply very, very directly to 3001 as well. So David, maybe could just say a word or two about some of the contraction of what would be a standard sort of checkerboard study to 3001.
David Lebwohl: With these two parts, the LNP and the AAV, we’ve learned a lot already about LNP, the ability to go to a particular site and target that site. And what we’ve learned from both the 2002 and 2001 program is that we can achieve essentially every, every allele being targeted with this so that we can open that up for the contribution that then AAV will make. We think this more as we have a good idea of the LNP dose and the variation will be more in terms of how much AAV is needed to optimally get expression of alpha-1 antitrypsin. Again, our goal is to get normal levels. That’s what we’ve achieved pre clinically and that’s our goal clinically as well.
Operator: The next question comes from Joon Lee with Truist Securities.
Unidentified Analyst: This is [indiscernible] on for Joon, staying on ATTR. So assuming positive update from HELIOS-B possibly late June and July. How does a third generation RNAi candidate with potential once a year dosing could change the treatment landscape in your view?
John Leonard : I would point out that things that follow us will be by definition after us. And we expect to be in a position where we will demonstrate the effect of our drug, which we think is going to be defining for the space. And our belief is that people will be comparing themselves to us as opposed to the agents that are out there. And regardless, it’s — I have not seen data that surpasses anything that we’ve presented thus far. Patients will still be receiving the drug chronically, which brings with it all of the issues that apply to that. And we think that the one and done approach is ideal for this patient set. And we are unique in that space. So, it’s important for patients to have different options, but nonetheless, we think that we will be setting the standard.
Operator: The next question comes from Silvan Tuerkcan with JMP Securities.
Silvan Tuerkcan : My mine is more strategically, maybe you can give us like 10,000 foot view on your strategy and the new tissues. I know you touched before on bone marrow and today a little bit on cystic fibrosis. But within all of these tissues that you’ve mentioned, which ones are closer to IND enabling studies, which ones are further along and how should we think about those programs coming to fruition over the next couple of years towards moving towards IND?
John Leonard : Thanks for the question. It’s an important one, but I don’t want you to think it’s a horse race and we give updates on the individual laps that, these relay races run. All of these tissues are very, very important. It really goes back to the philosophy and the strategic intent that has been the basis of the company since we first set out. It’s a very deliberate approach that thinks about delivery and editing technology. So, as is apparent, we started out with knockouts and the liver. What you see with the 3001 program is a gene insertion into the liver. We have technology to add to that in the form of gene writing in the liver. And the goal has been to take these various editing technologies, imply them to diseases that reside outside deliver.
And as Laura has mentioned earlier, we do that with collaborators where people have technologies that can supplement our own and take us to places that we may not be able to get there by ourselves. We’re excited about the work with Recode. We’re doing work with sparing vision. We have collaboration as with Regeneron. Each of these tissues, five of them that were delineated earlier, have very important diseases with large populations with unmet medical need. Some of those opportunities surpass what we see in the liver at the current time. And so, all of them benefit from the common approach from an editing point of view. And all of them are being resourced very, very aggressively to get to those preclinical development candidates.
Operator: The next question comes from Steve Seedhouse with Raymond James Financial.
Timor Vanicus: This is Timor Vanicus on for Steve Seedhouse. Congrats on rapid enrollment in Phase 2 magnitude study. One thing we would like to clarify is, what type of patients are expressing more interest in this study? Is it patients who have no access to any treatment, patients who couldn’t enroll under the trials or patients on the parameters or some other category? And one other thing we’d like to clarify is what is the screen failure rate? So out of the 40 patients that are screened, what proportion do you think will be dosed?
John Leonard : Thanks for the question. We’re not going to go into the details of screening failures and as I said earlier, number of sites and patients for sites and all that. That’s our work to do. And we’ll share as appropriate as we go forward. But David, is there any general insight you can provide in terms of the type of patient that’s coming or not coming into the study at this point?
