This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk02: the purview of Lilly. I am led to believe that things they take into Phase II, they tend to present the Phase I data of, and I look forward to that coming to pass.
spk05: Okay. Thanks very much. Thank you. Our next question comes from Ed Arce with HC Wainwright. You may proceed with your question.
spk01: Hi, good morning, everyone. This is Thomas here asking a couple of questions for Ed. At first, perhaps, can you share the thoughts on the competitive dynamics of being the second entry in NIA for PH1? And then also, can you go over some details of interaction with the FDA ahead of the NDA filings?
spk02: Sure. I'll take the first part of that, and then with respect to interactions, I'll pass over to Sri to answer that question. So there is a lot of unmet medical need in PH1, and there are many patients both in the U.S. and ex-U.S. that have yet to be diagnosed. So we expect the patient universe to be growing as diagnosis increases. We believe our monthly self-administered pre-filled syringe dosing regimen provides a particularly convenient and empowering dosing regimen for patients that are for customer research, so to speak, as we believe shows to be something that's highly desired. So we think, combined with the data that we have in PH1, there's a pretty compelling rationale for people to choose Nidozarin who are freshly diagnosed. When it comes to patients that are currently diagnosed, of course, many of those are in the process or have already gone on Oxlumo. The data for Oxlumo suggests that about 50% of patients do not achieve their oxalate reduction goal of normalization, and we think that those patients are likely going to be open to trying an alternative product to see if they can achieve their goal. For patients who are well-controlled and achieving normalized oxalate on Oxlumo, I think it's fairly unlikely you'll see a switch in that case based on convenience alone. So I think that's really how the landscape sort of plays out. And to the extent we really are having a lot of interest in that program for commercial out licensing, I think that story is resonating with the commercialization, potential commercialization partners. Cherie, do you want to talk about our interactions with the FDA?
spk04: Yeah. Thanks, Doug. So, as you know, in August, we revised our strategy to focus on seeking approval for Nidosoran for the treatment of PH1. We believe that the potential approval is supported by a clinical data package that consists primarily of the data from Phiox2 in which, as you know, Nidosoran achieved strong statistical significance for efficacy in PH1. Subject to our ongoing discussions with the FDA, we intend to submit additional efficacy data from our open-label extension study, Phiox3. We are currently processing the data and believe that we have collected all the data we need to file. So given this and subject to our ongoing discussions with the FDA, we expect to submit our NDA in Q1 of 2022 versus the original plans for December this year.
spk01: Okay, got it. Thanks. Thank you both for the additional details. Perhaps another question from us for DCR-AUD. While phase one is ongoing, can you share some initial thoughts on possible efficacy endpoints for phase two and beyond?
spk02: So the nature of the way DCR-AUD works is it provides physiological feedback to patients who consume alcohol. when they're in the process of treatment, to help themselves limit their alcohol consumption. And so the really relevant endpoint is what we would call a harm reduction endpoint, where it reflects that people have fewer days where they drink heavily. This is as opposed to abstinence, you know, not starting to take a drink. Abstinence would be appropriate for something that works at the level of trying to reduce cravings. whereas DCR-AUD, working at the level of providing feedback for those who give in to their cravings, is one where you would expect to see fewer days of heavy drinking. And so the reduction in heavy drinking days, also sort of, as I said, known as a harm reduction endpoint, is what we will be tracking in Phase 2, and what we expect will likely be the regulatory endpoint for approval in the U.S. and Europe.
spk01: Got it. Pat, one quick one. Does the cash runway include spending for the new extrahepatic program?
spk05: Yes, it does include the preclinical programs that we'll announce, as well as everything that's in the pipeline today.
spk02: We have planned a fairly aggressive introduction of new programs in our spending over the next several years, and that is fully included in our runway calculations.
spk01: Got it. I'm just going to thank you again for taking our questions, and we look forward to the unveiling of the new extra hepatic program.
spk05: Thank you. Our next question goes for Madhu Kumar with Goldman Sachs. He may proceed with your question.
spk06: Good morning, everyone. So thinking about alpha-1 and atrypsin, PIZZ, liver disease, kind of at a big picture level, what do you guys consider clinical proof of concept for patients kind of clinical benefit in the setting of that disease?
spk04: Hi, Madhu and Shree. I mean, you know that this is a rare disease, so I think that the evidence of efficacy is going to come from looking at improvements in liver histology, soluble biomarkers, and imaging. Given that the actual clinical endpoints of progression of, you know, ascites, hepatic encephalopathy, need for liver transplantation, are going to be hard to track in a clinical trial. Those are eventually the outcomes that matter. But in this program, I think establishing that our therapeutic hypothesis that reducing the mutant protein in the liver results in restoration of hepatic homeostasis and a return, either reduction in progression or reversal of some of the injury will be predictive of the clinical outcomes. But the primary basis is going to be on the basis of improvements in liver function, histology, and other markers.
spk06: Yeah, Sri, so on that point, how do you think about the variability in liver fibrosis in ZAAT patients and how much like the kind of more biochemical type parameters, things like Z polymer formation, Z globule deposition are going to be kind of more useful surrogates compared to fibrosis histology assessment per se?
spk04: Yeah, I mean, I know you follow the MASH literature, so we know that the hard end point of F-scores and changes in those with high placebo responses are a challenge. So I actually fully expect, and that's how Estrella has been designed, that it'll be the concordant movement in a beneficial direction for a variety of biomarkers that include both the soluble ones that you described, histological ones like reductions in globule, reduction in inflammation, reductions in liver enzymes, and an imaging biomarker like we are using MRE as an option as well as FibroScan to look at sort of overarching what's happening in the liver as a whole in terms of reductions in fibrosis or tissue resistance, if you will, to ultrasound. It will be a collection of those parameters, and I think that's part of the core discussions that we expect to have with regulators. We also expect to learn from what our competitors plan to do.
spk06: Okay, and then one last one. On the NADOSA and NDA submission, so you mentioned kind of pending ongoing pre-NDA interactions with the FDA. Is there any specific issue that's been raised as part of the kind of pre-NDA discussions, or is it just kind of like standard processes of NDA filing?
spk04: Well, I mean, look, you know the process, right? We got our PH1 data. They were very strong. As part of our normal routine, we engaged with the division for the discussions on now the NDA is getting ready. It's an ongoing discussion. We got feedback, no concerns on safety, and we are evaluating additional information that we believe we've already collected. And that's the sort of active process that's ongoing right now.
spk06: Okay, thank you so much, everyone.
spk05: Thank you. Our next question comes from Mayank Mantani with B Riley Securities. You may proceed with your question.
spk03: Hi, this is Yuan Zhi for Mayank. Congratulations on the progress in the last quarter. Thank you for taking our questions. Just a follow-up on the HPV questions. Understand the exact targeting position in the HPV genome is different. Can you remind us your target and any potential different impact you would expect versus Janssen's program? Thank you.
spk02: Sure. Thanks for bringing this difference up. There is some molecular differentiation between our approach and the approach of the program that Janssen is developing. So as I think many people who are deep in HPV recognize, there are four genes in the HPV genome, three of which are structural and one of which is regulatory. And the way the genes overlap and the transcripts for the genes map out One has the option of trying to hit all four at the same time or hitting three out of the four. And, of course, we evaluated that during our development. The Janssen program hits three out of the four, as I understand it, using two siRNAs and a ratio that hasn't been disclosed to my knowledge, whereas we use a single one that targets three out of the four. We did a pretty deep analysis in what we believe is the highest fidelity mouse model of HPV, recognizing this is not a mouse virus, but there are techniques that you can do to generate viral replication in mice. It's not an active ongoing infection, but viral replication intracellularly, and saw a distinct difference between three versus four gene suppression based on the status of this one, this fourth regulatory only protein. And when you don't silence it and you have an overabundance of that regulatory protein in the mouse model, it led to a longer duration suppression of S and a deeper suppression of S antigen. And this is due to sort of toggling between producing S antigen decoy particles or producing actively infected virus, of course, which new takes care of very, very effectively. I'd say we didn't see as dramatic a difference in our phase one human study, single dose. Well, four doses actually in patients, but it was a limited duration study. But we're still evaluating the duration there. To the extent that that mouse model shows an actual regulatory difference between three and four, the implication is that we should get better sustained S suppression and potentially a better human immune response due to that S suppression from the three versus four. This may be a subtle difference at the margins, or it may be an important difference. We'll see when it comes down to functional cure rates in the phase two. But we're pretty confident, at least at the animal model level, that we've tapped into some real viral biology around the regulation of S by targeting three versus four and having a relative overabundance of that regulatory protein in order to maximize the chance of the patient's immune system mounting a successful response against the virus, which we think is critical for the ultimate functional cure and truly eliminating the virus from the body.
spk03: Yes, thanks for the helpful color. I understand NUCC is very important as the part of the combination. Just want to hear your comments or thoughts. If you could add another part, another arm of therapy to the combo therapy you have, what would be an ideal one to generate more synergies? Thank you.
spk02: The ideal third combination partner alongside sRNA and NUCC is an immune system activator. to help refresh the exhausted immune response and drive T-cell-mediated elimination of infected cells that carry CCC DNA. That is the, to the extent we have proof of how to generate functional cure, the proven way, nuke and interferon being that proof, a small number of patients. But we believe that with an siRNA, particularly given its suppression of S, you can really drive that number up. So, I think that's the way to go. There are two triple combination cohorts like that in the clinical program that Roche is pursuing with RG6346, one with PEG interferon, Pegasus, of course, their long-time interferon product, and the second with their in-development liver-activated TLR7 agonist.
spk03: Yes, thanks for the, Connor, thank you.
spk05: Thank you, and I'm not sure of any further questions at this time. I would now like to turn the call back over to Doug Fanbrough for any further remarks.
spk02: Thanks, everyone, for paying attention today and all your questions. We're in a really strong position financially. We're in a strong position with our technology and our pipeline. We have some really exciting stuff coming. So I feel really good about our prospects here. Thanks a lot. Bye-bye. Thank you.
spk05: This concludes today's conference call. Thank you for participating. You may now disconnect.
Disclaimer