Q1 2025 Wave Life Sciences Ltd Earnings Call
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Speaker Change: Good morning and welcome to the WAVE Life Sciences first quarter 2025 earnings conference call.
Speaker Change: At this time, all participants are on the listen only mode. As a reminder, this call is being recorded and webcasted.
Speaker Change: After this presentation, there will be an opportunity to ask questions. To ask questions, you may press star and one on your touchstone telephone. To withdraw your question, you may press star
Speaker Change: I now turn the call over to Kate Rausch, Vice President Investor Relations and Corporate Affairs. Please go ahead.
Kate Rausch: Thank you, operator, and good morning to everyone in the call. Earlier this morning, we issued a press release, outlining our first quarter 2025 earnings update, including progress updates for ODCB and AHEB clinical trials.
Speaker Change: Joining me today was compared remarks for Dr. Paul Bolno, President and Chief Executive Officer, Dr. Eric Ingelsson, Chief Scientific Officer, and Kyle Moran, Chief Financial Officer.
Speaker Change: Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause or actually result to differ materially from those described in these forward-looking statements.
Speaker Change: The factors that could cause actual results differ are discussed in the press release issue today and in our SEC filing. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Paul.
Paul Bolno: Thanks, Kate. Good morning, and thank you all for joining us on today's call.
Paul Bolno: For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicine to transform human health.
Paul Bolno: With our clinical pipeline progress over the last 12 months, we've made significant strides towards realizing this vision, as we rapidly advanced our inhibitio obesity, AATD, DMD, and HD programs, demonstrating the impact of our novel and proprietary oligonucleotide chemistries in the clinic . . . .
Paul Bolno: It is our unique platform that has enabled us to assemble our multi-modal pipeline. Pioneer RNA editing and most recently advanced
Paul Bolno: In just the past two months since our fourth quarter update, we've continued the positive momentum across our pipeline by delivering the first 48-week forward 53 clinical results of WVE and 531 for DMV that have put us on track for our first NDA filing.
Paul Bolno: We've also demonstrated our consistent execution by advancing our obesity and AATD clinical trials towards multiple meaningful data and inflection points this year.
Paul Bolno: I'll begin with an update on these ongoing clinical studies and then review our recent positive results in DMD.
Paul Bolno: Starting in obesity, we are continuing to make tremendous progress in our in-lite clinical trial with WVE007, our GALMEC SIRNA and HIVEN-E candidate, designed to deliver healthy, sustainable weight loss.
Paul Bolno: Despite the rapid ascension of GLP-1s as standard of care, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability, including GI side effects and high discontinuation rates.
Paul Bolno: With an ability to deliver sustainable, healthy weight loss, with preservation of muscle and without the common negative side effects, increasingly associated with GLP1s
Paul Bolno: WVE-007 would unlock the next frontier in obesity treatment for more than 1 billion people living with obesity globally.
Paul Bolno: Leveraging human genetic insights, WAVE 007 is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass within frequent dosing of once or twice a year.
Paul Bolno: Our preclinical data on 007 have corroborated the strong genetic evidence for the inhibitory target. With just a single dose of WVE-007, we've demonstrated weight loss on par with stomach lootide and importantly, without suppressing food intake or loss of muscle mass.
Paul Bolno: We've also shown synergies with GLP1s, including as an add-on for individuals requiring greater weight loss, or who cannot tolerate high doses of GLP1s.
Paul Bolno: And notably, we demonstrated WVE 007's potential as an off ramp to GLP1, enabling long-term healthy weight maintenance.
Paul Bolno: This maintenance approach would avoid the weight regain that is common when discontinuing GLP1s and the associated metabolic risk of weight cycling
Paul Bolno: We are advancing WVE-007 in the in-like clinical trial in overweight and obese but otherwise healthy adults with a BMI between 28 and 40.
Paul Bolno: Today, we can share that we have completed dosing in the first two single dose cohorts of the study and remain on track to deliver initial data from the trial in the second half of this year, which will include safety, tolerability, and early changes in body weight as well as biomarkers reflective of healthy weight loss. [inaudible]
Paul Bolno: Turning to WVE-006, our Galnac RNA-editing oligonucleotide, or AMER, for Alpha-1 antitrips and deficiency.
Paul Bolno: WVE 006 is designed to be the first treatment for ATD that addresses the root cause of the disease with a convenient, subcutaneously dose therapeutic. Thank you, Eric.
Paul Bolno: WVE-006 does not require IV administered LNPs or complex delivery vehicles like other treatments and development
Paul Bolno: And by editing at the RNA level, WVE-006 differs from DNA editing technologies which rely on hyperactive, exogenously delivered artificial enzymes [inaudible]
Paul Bolno: Preclinical data has clearly demonstrated DNA-based editing results in irreversible collateral bystander edits and indels, and these known bystander edits must be taken into consideration when interpreting clinical results.
Paul Bolno: As a quick reminder, our Restoration Clinical Program began with dose escalation of WVE-006 and healthy volunteers and earlier this year, we announced the completion of the multi-dosing in the final cohort at dose levels greater than any plan for AATD patients in our Restoration 2 study.
Paul Bolno: In this ongoing Restoration 2 study, we are dosing individuals who have the homozygous P.I.Z. emutation.
Paul Bolno: We delivered a breakthrough in the field of Arne Medicine's last year with the first ever clinical demonstration of Arne editing in humans.
Paul Bolno: We observed a mean 6.9 micromolar circulating MAT and 10.8 micromolar of total AAT two weeks after a single dose in the first two patients in the 200 milligram colon
Paul Bolno: We also observed increases in AT from baseline as early as day three and as late as day 57, highlighting WVE-006's impressive durability of effect
Paul Bolno: In both Restoration 2 and the completed Restoration 1 clinical trial of healthy volunteers, we reported that O-06 was well-calerated with a favorable safety profile.
Paul Bolno: Following our announcement last year, interest in our study remained very high. In the first quarter, we initiated multi-dosing in the first cohort of breast duration 2, where patients are receiving 200 mg of WVE 006 every other week.
Paul Bolno: This dosing interval is consistent with our preclinical data, but I'll remind you that our proof of mechanism clinical data suggests the potential for monthly or less frequent dosing intervals
Paul Bolno: Dosing is also underway in our second single dose cohort at 400 milligrams
Thanks for watching!
Paul Bolno: Looking ahead, we are on track to share our comprehensive updates from restoration to this year, with data from the complete 200mg multi-dose and single-dose cohorts expected in the third quarter, and data from the complete 400mg single-dose cohort expected in the fall. We are on track to share our comprehensive updates from the complete 200mg single-dose cohorts expected in the fall.
Paul Bolno: We believe this higher single dose cohort coupled with the multi-dose 200 milligram data will give us meaningful insights into extending the dose interval as our pre-clinical and clinical data support deep potential for extended dosing intervals and subsequent cohorts. [inaudible]
Paul Bolno: These data will also inform the therapeutic potential of WAVE 006 and our pipeline of RNA-editing programs.
Paul Bolno: We are sharing preclinical data from these programs at multiple medical meetings in the second quarter, and expect to share additional new preclinical data from our hepatic and extra hepatic RNA editing programs through the remainder of this year.
Paul Bolno: We are on track to initiate clinical development of new programs in 2026.
And now turn to WVEN531 for DMD. And now turn to WVEN531 for DMD.
Paul Bolno: Since March, we have been actively engaged with the DMG community, sharing our exciting 453 clinical results.
Paul Bolno: These data have supported at WVN531 as a best-in-class and important new therapy adoption for boys with Exxon 53 and men of both DMD.
Paul Bolno: Following 48 weeks of treatment with WVE and 531, we observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks.
Paul Bolno: We also saw additional functional benefits observed in other outcome measures including NSAA.
Paul Bolno: With biopsies taken after 24 and 48 weeks of treatment, we were able to evaluate muscle health over time.
Paul Bolno: We saw the first ever demonstration of substantial improvements in muscle health with ex-unskipping, including a statistically significant reduction in fibrosis and decreases in CK and circulating inflammatory biomarkers [inaudible]
Paul Bolno: In addition, we've also observed clinical evidence of myogenic stem cell or satellite cell uptake of WVE and 531 earlier in our trial.
Paul Bolno: This is particularly notable as myogenics themselves are the progenitor cells for new myoblasts which would support the improvement in muscle health and muscle fiber maturation we observed at 48 weeks
Paul Bolno: We are not aware of any other clinical data for Exxon skippers or gene therapy that have been able to demonstrate myogenics themselves uptake . . .
Paul Bolno: Distrophant Expression, Average 7.8% between the 24 and 48 week time points with 88% of boys above 5% Average Distrophant.
Paul Bolno: WVE-N531 was safe and well tolerated with no serious adverse events.
Paul Bolno: GMD is a devastating disease that impacts individuals early in life. Each year, there are approximately 20,000 new cases of DMD with up to 10% amenable to X on 53-scripting. There is an urgent need for more effective and safe therapeutic options for patients.
Paul Bolno: Despite the limitations of currently marketed therapies, sales of Exxon skipping therapies were about $1.1 billion in 2024. Notably, up to half of Exxon 53, 51, and 45 patients remain untreated with Exxon skipping therapy.
Speaker Change: which, through our conversations with KOLs, are due in a large part to the burden of weekly dosing and limited evidence of benefit.
Speaker Change: Our data within 531 strongly demonstrate its potential to be a best-in-class treatment for boys amenable to X-on-53 skipping.
Speaker Change: Following a positive and productive meeting with the Cedar Division of the FDA on our 24-week data and initial plans for our confirmatory trial, the FDA has confirmed to us that the accelerated approval pathway with Distrophant Expression as a surrogate endpoint remains open. [inaudible]
Speaker Change: We are aligned with the agency on next steps for N531, and we intend to submit an NDA in 2026 for Accelerated Approval of N531 with a monthly dosing regimen.
Speaker Change: In the interim, we plan to continue to engage the agency with our new 48-week data, particularly in light of our statistically significant and clinically meaningful time to rise data, as well as other functional outcomes on our plan global confirmatory trial.
Speaker Change: To support a monthly dosing regimen at lunch, all participants in the extension portion of Ford 53 are receiving monthly dosing. And we are expanding the trial to include additional boys who will be dose monthly. Thank you very much.
Speaker Change: Beyond N531, we are advancing an excellent skipping franchise with candidates that leverage our besting class chemistry, and we anticipate filing CTAs for multiple candidates in 2026.
Finally, turning to WVE003 for the treatment of Huntington's disease. [inaudible]
Speaker Change: There is an urgent unmet need in HD, as the disease impacts more than 200,000 people in the US and Europe alone, and there are no disease modifying therapies available.
Speaker Change: HD is a devastating autosomal dominant genetic disease that impacts multiple generations of family members, and is sometimes compared to having Alzheimer's Parkinson's and ALS all at once. [inaudible]
Speaker Change: Using our platform's specificity of stereochemical control and best-in-class chemistry, we developed WVE003 using a first-in-class allele selective approach.
Speaker Change: By reducing mutant hunting tin at the mRNA and protein level, WVE 003 addresses the underlying drivers of neurodegeneration
Speaker Change: And by sparing wild side protein, which is critical to the health of the central nervous system, WVE 003 is uniquely positioned to address the false spectrum of HD, from early asymptomatic stages to the onset of symptoms and beyond.
Speaker Change: In our Select HD trial, we demonstrated the impact of our novel chemistry and a Leo selective approach as we observe potent and durable mutant Huntington reductions of up to an industry leading 46 percent and preservation of wild type Huntington with just three doses.
Speaker Change: Importantly, we observed a statistically significant correlation between a leo-selective mutant Huntington reductions and slowing-of-caudite atrophy, marking the first time this correlation has been observed in HD.
Speaker Change: This correlation is particularly notable as Codate is one of the primary areas where HD manifests in the brain with atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2-4% per year.
Analysis have also demonstrated that caught a loss correlates with clinical outcomes.
Speaker Change: At the beginning of the year, we shared our own internal analysis. Thank you.
Speaker Change: which investigated natural history data sets including track and predict HD and observed that an absolute reduction of just one percent in the rate of caught atrophy is associated with a delay of onset of disability by more than seven and a half years.
Speaker Change: This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of quadratrophy as a primary endpoint for efficient clinical trials.
Speaker Change: These data, along with the full clinical results from Select HD, were both part of our engagement with FDA last year that led to supportive initial feedback.
Speaker Change: We are continuing to prepare for a global potentially-registerational phase 2-3 study of WVE-003 in adults with SNP-3 and HD using Codate as a primary endpoint.
Speaker Change: and we remain on track to submit clinical trial applications, including an IND application for this Phase 23 study in the second half of this year.
Speaker Change: And we are actively engaged in discussions with prospective strategic partners. With that, I'll turn the call over to Eric to share more detail on our in Hibony program and emerging Holy Island pipeline. Thank you very much.
Erik Ingelsson: Thank you Paul, and thank you to everyone joining us on the call today. I'll begin by discussing our in the beneath program for the evening.
Speaker Change: As Paul shared earlier, there have been numerous efforts to develop therapies in the obesity space. So it's important to examine out how our intervening gap against RNA approach differs from current treatments, such as GLP1 agonist and other therapies in development.
Speaker Change: Among the reasons that I'm very excited about this program is the target's strong foundation in human genetics.
Speaker Change: Several large human beings that have found the carriers of heterocellular lots of function variants in the need genes have favorable metabolic profiles including reduced abdominal obesity and visual fast, serum triglycerides, APOB, fasting glucose, HB1C and decreases in several measures of liver disease. [inaudible]
Speaker Change: Importantly, these carriers also have reduced risk of type 2 diabetes and coronary heart disease.
Speaker Change: So essentially the outcome studies have already been conducted with this target using nature's experiment.
Speaker Change: This is particularly notable for the development of WB-E007, as targets supported by Humie Unix are an average associated with a two to four times higher probability of success in drug development.
Speaker Change: Importantly, in addition to evidence from June genetics and our convincing preclinical data, internal work has also demonstrated a strong correlation of circulating active in e-levels with the MI in blood samples from humans, providing an additional confirmation of the importance of this mechanism in driving obesity.
Speaker Change: In the many years, a gene predominantly expressed in liver that produced the Hepatocaine active in e. Activity has done secreted from the liver and binds to receptor and adipose tissue called ac7. With easy access to energy-dense food in modern society, liver in e.M. RNA is up-regulated, resulting in higher circulating active in e-levels which promotes increased fat storage and abdominal obesity.
Speaker Change: We chose to target the ligand in the beginning over the receptor out of seven for several reasons. First, using our best-in-class organified chemistry to turn off the protein production directly at the upstream source is the most efficient way to down-regulate activity of this ligand receptor pair. And second, galmic conjugates allow for high-level specific and efficient organ delivery cells.
Speaker Change: In the beginning, silencing a deliver leads to lower circulating activity levels and less out of certain activations and facts. This results in increased adipose-like policies, decreased abdominal obesity, and ultimately healthy weight loss and an improved cardiometabolic profile. [inaudible]
Speaker Change: We're continuing to make great progress in in light as we've already completed dosing in the first two courts and we look forward to sharing data from the trial in the second half of this year.
Speaker Change: This data will include safety, tolerability, and biomarkers reflective of healthy weight loss, and we'll also be looking at early changes in body weight [inaudible]
Rather than the centrally acting appetite regulation. [inaudible]
Speaker Change: Therefore, delivering a similar magnitude of pound-by-pound weight loss at a comparable time on treatment suggests substantially larger effects on fast loss than the current standard of care.
Speaker Change: Combining this with a retention of skeletal muscle, which has a crucial role in Luca's update, highlights the potential of this program to result in profound improvements of incidence sensitivity, and lower risk for tattoo diabetes and cardiovascular disease.
Speaker Change: Upcoming data will provide us with valuable insights into WVE-007's potential to transform the into the treatment program.
Mal, Turning to Emerging Pipeline
Speaker Change: Our WEE 006 proof of mechanism data last year demonstrates that we could drive impressive potency under ability of effect in a clinic with an aimer. Now with the advent of RNA editing in the clinic, we have the privilege of helping define how this new modality is applied.
Behind WBE 006, we're containing advance of Hollywood. We're on the...
Discovery Pipeline addressing both hepatic and extrapatic targets
Speaker Change: As with WBE-006, our pipeline programs are strongly supported by human genetics, all for novel ways to treat diseases in areas of high unmet need, and feature readily accessible by a marketing approach that sets pharmacodynamics, along with established regulatory paths.
Speaker Change: We unveiled three of these programs that our research day last fall, which is galactic conjugation.
Speaker Change: These programs included our PLMP3 RNA correction approach aimed at addressing the 9,000,000 I148M homozygous individuals in the U.S. and Europe with a variety of liver diseases.
Speaker Change: NRLD, Alora Fregulation, and AFAB Correction Programs, which together would address approximately 1 million people living with heterostigals, familiar half-coloured Selimia, in the US and Europe .
Speaker Change: You should also be noted that the LDL-RF regulation approach has an opportunity for a substantial indication expansion to individuals with death intolerance or prior cardiovascular disease with uncontrolled LDL cholesterol.
Speaker Change: In addition to these programs, we also have shared preclinical data, highlighting our ability to direct, silencing, and add a thing to high priority, extra hepatic tissues including CNS,
Speaker Change: One application of these capabilities that we shared at our research day last fall was our ability to fly our aimers to support RNA-editing across the enhanced issues in red syndrome.
Speaker Change: And this devastating disease, there are 168 ex-mutation in the MSCP-2 gene on the X chromosome leads to neurodevelopmental disorder in females.
Speaker Change: R-Amers, which are designed to edit the R-168's ex-mutation to generate full length MS-C-2 protein with an R-168 W substitution, shows substantial increases in protein expression throughout the CNS in a humanized mouse model. [inaudible]
Speaker Change: Further, next week is in an oral presentation at the ASGCC 28th Annual Meeting. We'll share additional preclinical data demonstrating proof of principle for amers in long indications, including specific fibrosis.
Speaker Change: Enthusic fibrosis, the W1282X, and the G542X non-submissations results in stop codons to prevent protein production.
Speaker Change: Without the program, there is no way for current small molecule approaches that impact these individuals.
Speaker Change: The preclinical data we plan to share next week demonstrate that in CSCRW1282X The preclinical data we plan to share next week demonstrate that in CSCRW1282X
Speaker Change: Schumann Bronkel, Bronkel Epithelial Cell, CF-CR-AMRS increased expression of CF-CR mRNA-3-fold and restored up to 50% of functional wild-type CF-CR protein levels which is well about the expected threshold to improve lung function.
Speaker Change: We're actively engaged with the CS Foundation, as our aimers have the potential to edit and restore protein production which would be incredibly meaningful for this segment of the CS community that currently have no treatment options
Speaker Change: As we look to the remainder of the year, we plan on sharing new pre-clinical data from our emerging pipeline in 2025, highlighting our past initiating clinical development of additional Hollywood programs in 2026.
Speaker Change: For that, I'd like to turn the call over to Kyle to provide an update on our finance, Kyle. Thanks, Eric. Our revenue for the first quarter of 2025 is $9.2 million, and compared to just $12.5 million in the prior year quarter.
Kyle Moran: The Euro be a decrease was attributable to the timing of revenue recognized under our collaboration agreement with GSK.
Kyle Moran: Research and development expenses were $40.6 million for the first quarter of 2025 as compared to $33.4 million in the same period in 2024 .
Kyle Moran: This increase was primarily grown by spending one of our our inhibited programs, our RNA-and-a-and-a-programs, as well as competition-related expenses, including share-based competition
Kyle Moran: Our G&A expenses were 18.4 million dollars for the first quarter in 2025, as compared to 13.5 million dollars in a fire year quarter, primarily related to share-based compensation at most best of the weeks.
Kyle Moran: As a result, our net loss was $46.9 million for first quarter of 2025, as compared to in that loss, $31.6 million in a prior year quarter
Kyle Moran: We ended the first quarter of 2025, it's $243.1 million in cash and cash for those
compared to $302.1 million as of December 31st, 2024.
Kyle Moran: We expect that our current cash and cash equivalent can be sufficient fund operations, which is 2027, is important to note the potential future milestones and other payments to wave under our GSK collaboration, and not included in our cash runways. I'll now turn the call back over to Paul, closing the amounts.
Thank you, Kyle.
Kyle Moran: Our consistent execution in the clinic has positioned us to deliver on multiple key milestones throughout 2025, including the first demonstration of healthy weight loss within Hibini, and the first multi-dose data in RNA editing.
Kyle Moran: We look forward to keeping you updated on our progress throughout the year as we continue to re-imagine what's possible for patients. With that, I'll turn over the call to the operator for Q&A, operator.
Thank you
Speaker Change: We will now begin the question at the session. To ask a question, you may press star and one on your telephone keypad.
Kyle Moran: If you're using a speakerphone, please pick up your handset before pressing the keys [inaudible]
Kyle Moran: If at any time your question has been addressed you would and you would like to withdraw your question please press star and then two at this time you will pause momentarily to assemble a roster. Thank you.
Kyle Moran: We have the first question in line of Joon Lee from Chris Securities, please go ahead.
June Lee: Thanks for the updates and for taking our questions. For the Inhibit-E program, what's the trigger for data disclosure, which you need to have completed dosing in all five SAT cohorts for the disclosure or ones you have reached some other internal threshold and have a quick follow-up question.
Speaker Change: Yeah, thank you for the question, Joon. So, the way the current study is running is, as we said on the call today, the first two cohorts are dose, that's very important as it puts us on track for delivering data. The disclosure will be triggered as you'd imagine, we'll be looking at time points. [inaudible]
Speaker Change: One month, three months, six months. And so we have an internal disclosure cut off where we would do a cut of the data to disclose. And we said target engagement, weight loss and biomarkers. We have an updated which one of those would be the time point for that disclosure. Thank you very much.
Speaker Change: And then, you know, you have a few drugs slated for accelerated approval, including for D&D and Huntington's, can you confirm that they are all under cder and not cder and any risks to the accelerated approval process for you guys?
Speaker Change: Yeah, I think to elevate Nancy your first question, it is Cedar, not C Burr. I think when we talk about genetic medicines, they brought context, I think we have to recognize there are different divisions that still cover the concept of looking at genetically defined medicines, but we are a big small molecule, not a gene therapy or a protein biologic.
Speaker Change: What's also important to note is our conversations as we've exchanged the agency have not changed, so the cadence of communication.
Remains consistent.
Speaker Change: The discussions that we have shared with you all publicly have been aligned around the Accelerator Approval Pathway and nothing is suggested that there's a change to that. I think it's also important to step back and reflect that we've also taken a comprehensive approach to advancing our programs if we think about the DMD.
Speaker Change: This is not just a discussion on dystrophin, it's a conversation on dystrophin, muscle health, and ultimately as we've shared, statistically significant and clinically meaningful outcome benefits. And so the nature of the discussion that we'll have around the 48 weeks is really around utilizing the concordance of clinical data along with biomarker. [inaudible]
Speaker Change: Same things true in HD, where it's not just about industry leading 46% reduction in mutant protein and wild side sparing, it's the consistency what we've seen in correlation of caughtate, which is the key anatomical endpoint. And so I think the comprehensive nature of our data will continue to support our filings and dialogue with the agency.
Speaker Change: It's like the squeeze one more in, you know, on the Huntington's program, you know, the recent data, very fresh data from Voto plan, the spice modulator. [inaudible]
Speaker Change: They seem to imply that the MRI of the audit may not be as consistent per their data, any thoughts there, and also they include the Stage 3, which I don't think you're including in your proposed Phase 2-3.
Speaker Change: You know, any thoughts based on that we see from that data. Thank you.
Speaker Change: Yeah, no, I think I look at that data in the context of...
Speaker Change: Tom Anderson, and other hand silencing approaches that have looked at imaging over time and it's difficult and I can't comment on their MRI quality of their patients in stage three and how those studies were run. [inaudible]
Speaker Change: What I can do is step back and say, when one looks at track and predict HD at the quality of MRI imaging and the consistency with which you can see changes, actually MRI has been highly consistent. And this isn't just around our own internal analyses, there have been analyses of an exico, there are debris team Jeff Long will publish soon his report from University of Iowa. And so MRI has been highly consistent. And so I think it is an opportunity for us.
Speaker Change: To really reflect now on a number of pan-silencing approaches that take down the healthy protein and really look at this as an opportunity at a real selective silencing on mutant reduction. Not the least of which is we've had substantially more mutant hunting tin per-
Speaker Change: Lowering, than any of the other programs. So again, the consistency with which we saw reduction of protein carling with caudate is a very different program.
and that's that's very helpful. Thank you so much.
Thank you
Thank you.
Speaker Change: We have the next edition line of Joseph Schwartz from Learing Partners, please go ahead
Speaker Change: Jenny Onford, Jo, thank you for taking our questions and congrats on all the progress.
Speaker Change: For Alpha 1, even with single dose data at the lowest dose that you've tested, you're getting to that previously established 11 microbeller threshold range for total AAC protein.
Speaker Change: First, do you think there are any additional benefits to getting above that threshold? And if so, at what point would there be no additional benefits? That's it.
Speaker Change: And second, can you talk a little bit more about the major pros and cons of RNA-editing versus DNA-editing and diseases like alpha-1? You pointed out bystander edits and reversibility as major points of differentiation in the past. We're just wondering if you think there are other things that an alpha-1 patient might consider if they were not have multiple options in the future. Thanks.
Speaker Change: Yeah, no, thank you for the question. And I think if we step back and say again, what's the target product profile? I mean, I think we've all talked about in the field of this concept of 11 microball or being similar to what the MZ patient has. I think it doesn't mean that there are an opportunity to continue to correct that protein over time. Not just for thinking about lung, but ultimately, how do we continue to clear hepatic aggregates more quickly, meaning prevent more aggregating protein and therefore drive that correction. So I think it's incredibly exciting that we're already at that threshold.
Speaker Change: with the lower single dose, but I think what's really in front of us. [inaudible]
Speaker Change: Semen Micromolar, being able to continue to push that M protein level even higher towards what could be a heterozygous level could still continue to improve the potential for clearing out the liver. And I think what's important is we follow that and what we saw in the Serpent A1 models early on. [inaudible]
Speaker Change: Was that the protein will fluctuate over time. It's important why we followed total just to see collectively get a sense of what's happening in the as a reservoir for what may be clearing out of the liver. [inaudible]
Speaker Change: And that's separate from the M protein which is being produced and secreted and protecting lung. So I think there's more opportunity ahead of us as we think about repeat dosing and higher doses to continue to drive that improvement towards nearly healthy. So it's incredible where we've started. And that's it.
Stepping back and thinking about.
DNA editing, you know, as you asked, verses RNA editing [inaudible]
Speaker Change: You know, I do think it's important to really note that distinguishable difference between what you get with bystander editing and indulge, either knocking out the frame of protein, so not producing it or producing protein, you know, with a bystander at it, you create a misfolding that protein. That can result in several things. One is obviously what's been talked about and what's been shared and some scientific...
Speaker Change: Poeter Presentations, which is, those isoforms can have very different efficacy in terms of the neutrophilolastase, that's inhibition acid.
So they can functionally behave as different proteins.
Speaker Change: Eng is also to note that this is a highly sensitive protein to mutations in terms of aggregation.
Speaker Change: So we don't know yet, and it'd be interesting to see whether or not the life forms of by-centred approach seems actually aggregate in the liver and therefore a trap and aren't getting out. So I think it's going to be important to study the impact of these by-centreds over time and the potential impact to these patients over time.
Speaker Change: I think the second piece is also less of DNA versus RNA. It's implied in DNA editing, because delivery is key and therefore the use of lipid nanoparticles. This is true for both DNA and RNA editing.
Speaker Change: Constructs that use LMPs, but you can get sporadic changes in ASTL, T-elevations just based on the lipinato particle alone. You can get accumulation of those particles and hepatic injuries. It's over in itself.
Speaker Change: We think about long-term for patients with hepatic insufficiency IV loading of LMPs over time is probably not ideal for the liver and so therefore that really fed into our approach between starting the program which was a GALNIC conjugated drug that doesn't require LMPs.
Speaker Change: and particularly to the specificity of not generating bystander isoforms for indents.
Thank you. It's really helpful.
Thank you
Speaker Change: We are the next official line of Eric Joseph from JP Morgan, please go ahead
Speaker Change: Hi guys, this is Ron on for Eric. Thanks for taking our question. I wanted to ask about this couple of analysis you're going to look at for AT expression in terms of you know protein concentration and its functionality, whether it's M or Z protein and to what extended the recent competitor, you know disclosure serves
Speaker Change: Does it serve as a roadmap for the type of endpoints you'd like to report? No.
Speaker Change: And then just another short one is specifically the readout, you know, disclosure before, was the A.T.
Speaker Change: We're the AT levels measured through turbidity or through LCMS. Thanks.
Speaker Change: Great. I think our disloyalters which preceded that of others, you know, was an update on proven mechanism. But I think, you know, it's the totality of data as we share. It's total protein.
Speaker Change: It's importantly M protein and looking at that which is edited protein [inaudible]
Speaker Change: and then it's following that over duration of time and so...
Speaker Change: The next update because we'll have both single and multidose data for the complete cohort will be a totality of understanding the dynamics of what happens with single dose intervals and that editing over time. And importantly, what happens with the
Speaker Change: repeat dosing, every time we've seen repeat dosing with PN chemistry we see that that tends to lead to more drug retention therefore not just higher potential production of protein but actually longer duration of activity and so we'll be able to plot those kinetics over time and I think it's important on the longitudinal side of the data to have the full disclosure we've seen with others that there's actually potential.
Speaker Change: with some of the even the DNA editors waning activity. So I think for us to have a complete data set that we can follow over time I think it's going to give us a very good opportunity to follow not just the potency but also the duration we have had and we shared before the last case inhibition work so again the functionality of the protein but again. [inaudible] I think it's going to give us a complete data set that we can follow over time I think it's going to give us a complete data set
Speaker Change: In the absence, and as we've shown that these proteins aren't bystandered, it is pure wild type. We wouldn't expect that to be different and non-functional. We shared that early, but we would just share the elastase inhibition to assay as part of that.
Speaker Change: We haven't shared data on the assay that we're using for the total rate.
Thank you.
Speaker Change: Thank you. We are the next session line of Jun-Jong from Birdbush. Please go ahead.
Yoon Jung: Hi, good morning. Thank you very much for taking the questions and a follow-up question on the ATD program.
Reporting, Steven.
Why do you divide the data set into two? [inaudible]
Yoon Jung: Separate Announcement, third quarter versus fall, and why don't you just combine data from both cohort into a more comprehensive data set? Do you think it's important to provide maybe some piece of data as soon as it becomes available? Thank you very much.
Speaker Change: It's a wonderful question that everybody always thinks about in holding back and waiting. I think what we can feel very confident on is
Speaker Change: The dough thing is patients are fully enrolled and we're going to deliver data on the multi-dotes and we have absolute specificity for the timing of that data set. It's a comprehensive data set and we believe in totality that's a very material data set so when we have that conclusion of that we'll share that data. [inaudible]
Speaker Change: Whether or not, and as we're enrolling the 400, I can't say, you know, that's why there's, I say, Paul.
Speaker Change: If that happens to move faster, it's not to say that we wouldn't be able to pull those in, but I think if we wouldn't-
plan to hold one data set back for the other.
Speaker Change: And we do believe that that 200 Multi is highly informative. Thank you.
Speaker Change: as we think about not just going forward for Alpha 1 and Detripsen, but it's also going to help us as we think about the other aimers in the portfolio and understand for the first time human modeling between a mouse to a non-human primate ultimately do a human repeat dose highly informative across the aimer platform as we advance other programs so understanding that that pharmacology. Thank you.
Speaker Change: It's going. It's going to be important. And yeah, I will say the 400 is enrolling very well. So I think at this point, you know, there is that opportunity to have that on the earlier side, but, you know, we'll provide updates in future. Thank you.
Speaker Change: Okay, then on the DMD program and would you expect to include monthly dosing data into the MD submission package?
Speaker Change: Yes, I mean that is the plan and based on our discussions with the agency, the plan is to have monthly dosing in the label. So that those updates on the extension expansion would match the anticipated filing timeline for the for that. We're also engaging the agency to discuss the 48-bit clinical data and discussing the have putting clinical data in the label as well. So we think about the comprehensive differentiation from other excellence, skipping therapies, the opportunity for monthly dosing, the opportunity.
Speaker Change: for high level of disturbance that's been seen as, and again I'm talking now about the commercial 53.
Speaker Change: patient population as we're going into that. The ability to show holistically change in improvement in muscle health, reduction in fibrosis and then clinical outcome measurements with safety that doesn't look different than standard of care is the real opportunity. We want to be able to capture that. Thank you.
Okay, great, thank you very much.
Thank you.
Thank you.
Speaker Change: And no. One can go ahead, sorry follow up on deals just take that one off just right away. So no not observing data, we just haven't disclosed where those cutoffs are going to be those are just the time points that are involved in the study, but no. We haven't broken out when we're going to cut it and we have a pre defined opportunity to look I mean, I think what's interesting is and I think.
Speaker Change: Sometimes people are on the late side of thinking about <unk>, but just to put it in context. If you think about the one three and six months in a placebo adjustment for G. L. P. One you've got about one 5% weight loss of one month about.
Speaker Change: Somewhere around 4% to three months at around 7% at six months and so we've got a real opportunity I think to define what the kinetics of inhibitor youre going to look like and recognizing that a grand Slam would be if we see similar to that where it's all fat and muscle recognizing 40% of that percentage body weight, Boston GOP ones.
Speaker Change: Is muscle I think we've got a real opportunity within a relatively short timeframe to substantially differentiate inhibin is a best in class healthy weight loss solution.
Speaker Change: Okay. So just to be clear you are not looking at blinded data and you already have a pre defined time cut off but you just haven't that's correct.
Speaker Change: Okay.
Speaker Change: Okay, and then just on DMD your comments around the initial plans for using dystrophin expression for accelerated approval are those plans locked in like do you have it in writing from the agency that that would be acceptable for an accelerated approval.
Speaker Change: Or is there any risk here that if we do get a new feeder had that would like to change things or has a different view on accelerated approval.
Speaker Change: For diseases like DMD.
Speaker Change: Is there any risk to that.
Speaker Change: Endpoint moving.
Speaker Change: Yes, we have in that conversation cedar in the division of Cedar responsible for DMD, commenting that dystrophin is a clinical surrogate endpoint. So that that's that's the division as it as of now that's their statement of dystrophin as a clinical surrogate endpoint for accelerated approval.
Speaker Change: I think as we continue to go forward with.
Speaker Change: I think we want to continue to bolster that support with our additional data like we have with GTR and other clinical endpoints to drive differentiation, but at this point the agency comment on dystrophin has not changed.
Speaker Change: Okay. So there.
Speaker Change: They're they're they're.
Speaker Change: Just to be clear their view is that's the endpoint right now, but it's not locked and correct. I mean, if we do get a new Cedar head, who has a different view there is potential for that to.
Speaker Change: Move correct.
Speaker Change: It's always and I think this is really important when agency established as something as a clinical surrogate endpoint.
Speaker Change: That's important right.
Speaker Change: Phoenicia, there have been approvals locked in on that and so the agency tends to be very consistent I think what we want to provide his continued support the agency as we've seen with the GTR data that again, there is a relationship between dystrophin and that endpoint I think were probably more apt to see.
Speaker Change: Is the agency pushing which is why is the confirmatory discussions are important is really designing to say.
Speaker Change: You still have to confirm that dystrophin as a clinical surrogate endpoint. So the pressure would come in.
Speaker Change: Much on existing companies and completing the confirmatory studies within a timely standpoint to do that I think it's why our assumption going into this is you need a substantially enrolling confirmatory study to prove to the agency that youll have the plans to commit to finish that study on the other side of that approval, but.
Speaker Change: The agency and a new head could come in and revisit it I think it's highly unlikely that they would overturn a precedent on a clinical surrogate endpoint, but more likely continue to hold companies to completing confirmatory studies to substantiate that and I think that's consistent with.
Speaker Change: The carry and the head of the FDA, saying, how do we accelerate new medicines that one hand, you can accelerate new medicines.
Speaker Change: Still and I think this is just an important notion you can accelerate medicines and whole companies to completing improving those endpoints and I think we're very much committed to both of those in the current data. We've generated this very much supportive that we can bring those two pieces together for once and DMT that we can see that dystrophin is creating healthier muscle is creating clinical outcome measurement change.
Speaker Change: And I think being able to put those pieces together, we can say that was of interest the agency of being able to connect those dots.
Speaker Change: We will obviously have an upcoming discussion on the 48 week data that is going to be informative how to build clinical endpoints to instill label.
Speaker Change: Okay Super helpful. Thank you very much.
Speaker Change: Yes. Thank you.
Speaker Change: Okay.
Speaker Change: Thank you we have the next question the line of Catherine Novak from June's Research. Please go ahead.
Speaker Change: Hi.
Speaker Change: Morning, Thanks for taking my questions.
Speaker Change: Thinking about the enrollment for the monthly DMD cohort, how many additional DMD patients do you expect that you'll need to ensure your monthly dosing regimen at launch and then following up on that as you enroll in the study and working with investigators are you seeing any indication that providers and maybe reassessing the risk benefit profile.
Speaker Change: Gene therapy in DMD.
Speaker Change: Yeah, I think the last point.
Speaker Change: The short answer is yes, I mean, I think in general I think there was a lot of questions in turns I think where the question is really come up and we have to remember that there are boys, who are amenable to exon skipping and there are boys, who are at risk, who arent and I think that's where we see some of the clinicians thinking about these different tree.
Speaker Change: <unk> are opportunities if.
Speaker Change: If they have a boy who is not amenable to exon skipping.
Speaker Change: Amenable to gene therapy, we might see them go there I think with the recent signals I think what we are hearing is where there is an opportunity for exon skippers that could actually be beneficial that there'll be an error on the side of thing where we should go with that approach. So we'll see how that ultimately.
Speaker Change: Translate into practice, but highly encouraged based on our discussions.
Speaker Change: With clinicians.
Speaker Change: Enrollment sorry going back to the enrollment side on the on the cohort one as we said we have 11 voice in the study rolled over onto the monthly dosing on the extension portion of the study and we would.
Speaker Change: Anticipate just for guidance on enrollment that that expansion cohort would equilibrate such that we'll have the total number of patients. If we think about filing similar to those other exon skipping 53 programs that filed microcapsule.
Speaker Change: Okay. Thanks, that's helpful and then.
Speaker Change: Thinking about the ATB program, how are you interpreting your increase in CMT protein versus being significant decrease in Z protein, what do you hypothesize that happening to the deep protein aggregate and deliberate with DNA base editing.
Speaker Change: Arnie.
Speaker Change: Yes, it's interesting and I'm glad you asked the question.
Speaker Change: We looked at all of our preclinical work and that was really what drove us to really dig into the aggregates is when we saw the secondary increase the protein the Z protein isn't being produced threat and proteins produce crediting the proteins actually coming into serum by a byproduct of breaking up the aggregates in the liver right. That's the reservoir that leads to that.
Speaker Change: The protein increases and so the fact that we are seeing that which correlated very much to what we saw in our preclinical models is highly encouraging of both the lung and liver applications of our RNA editing formats I think it raises into questions. In this kind of plateauing almost of protein without seeing those corresponding increases in again.
Speaker Change: Whether or not with DNA editors, whether or not theres increased protein actually aggregation deliver whether or not there's actually any breakdown of that protein from the liver and I think that's a great question that continue to be explored as these two technologies move forward and treating both lung and liver is what is happening to the Z protein that is aggregating and liver. So we can be very clear.
Speaker Change: Edited protein and protein increasing Z protein coming out of that reservoir, but I think it's interesting to us to continue to follow these overtime.
Speaker Change: Okay.
Speaker Change: Now maybe just to add this is also why we think it's important to focus on the am protium, because that's it's an easier a benchmark to compare across different approaches.
Speaker Change: Yeah that makes sense, thanks for taking my questions.
Speaker Change: Thank you.
Speaker Change: The next few from the line of Steve <unk> from Cantor Fitzgerald. Please go ahead.
Speaker Change: Alright. Thank you for the question. This is Nick on for Steve too for US first what does the distribution profile look like in lung tissue with your existing gamers are.
Speaker Change: And are there any novel modifications were conjugation methods, we're using here to optimize PK.
Speaker Change: Oh.
Speaker Change: Yes, I mean, one I'll refer you definitely did and we're happy to the R&D day deck was pretty comprehensive as we think about not just for <unk>, but also our SA RNA formats, where we saw incredible silencing and durability in CNS and muscle. So I think about the totality of the work that we've done on our platform context and driving distribution.
Speaker Change: Through a variety of cell types.
Speaker Change: Think about editing liver adipose sites and others and so.
Speaker Change: CNS and as Eric shared lung as well.
Speaker Change: How we drive that can be through pn variance and so these are modifications to the chemistry on the on the backbone separate from distinct Cowlneck like delivery. We also have activities delivering specifically to certain cell types in a way that would be similar to <unk> and we're excited to share those updates as we move into R&D day later this year, but I think the real opportunity.
Speaker Change: Continuing to see.
Speaker Change: We've optimized gallon that delivery and show that consistently we've removed gallon that can drove the editing and higher efficiency levels to a variety of very important tissues of which there's really strong genetic targets and.
Speaker Change: And we will continue to provide updates on that both in medical meetings as Eric Sheridan at GTC and others and then into the fall at R&D day.
Speaker Change: Understood maybe just.
Speaker Change: Yes.
Speaker Change: It's not that we don't need a conjugate for forgetting into learning, it's all about the chemistry optimization.
Speaker Change: The Pn chemistry, etc.
Speaker Change: Got it makes sense, okay. Thank you and for inhibitor Arrowhead as mentioned they intend to do quarterly dosing for their program.
Speaker Change: Just wanted to check your view on that given that you previously talked about way of targeting and every six months or annual dosing interval are you still confident in that strategy for waves or sort of southern that'll do it. Thank you.
Speaker Change: Yeah, Thanks, very confident in our strategy and I think that goes back to the preclinical data that we've had versus the preclinical data of our peers.
Speaker Change: The data that we have suggests much greater potency and durability, we shared that in the NAR paper a couple of years ago that we have 30 fold improvement in <unk> over the best in class SA RNA formats, and that's not just arrowhead.
Speaker Change: And so as we think about this opportunity and what it really provides his depth of knockdown, so that kind of amplitude potency, but most importantly durability. So we have a differentiated <unk> format and the other <unk> companies and we think this is a very attractive opportunity and place to apply it.
Speaker Change: Thank you.
Speaker Change: Thank you we have the next question the line of Roger song from Jefferies. Please go ahead.
Speaker Change: Hi, This is Josh on for Roger I had a follow up question for your <unk> program I just wanted to know what you think would be it. Thank you.
Speaker Change: Successful data readout, and what benchmark you're using for that as you can.
Speaker Change: Yes, I mean, as we shared before I mean, it's important to think about where the references are around the <unk> weight loss over these various time points. So if you're around 1151 month or 4% at.
Speaker Change: Three months in somewhere around 5%, 6% as you go into the six month time frame.
Speaker Change: Remember that those percent body weight losses at those various time points again.
Speaker Change: Sometimes I know we tend to think about this wave losses, one category, but if you think about the movement and even the FDA guidance at the beginning of the year around what healthy weight loss looks like in terms of fat loss versus muscle, 40% of those numbers on body weight loss are driven off of muscle loss, so a homerun and more likely a grand Slam as you see.
Speaker Change: Similar like we saw in the mouse weight loss that's all.
Speaker Change: All fat.
Speaker Change: That would be.
Speaker Change: Incredible I think the opportunity to still continue to see the fat loss component of that or more is also there but everything in the animal models suggest the similar cadence, but I think it's important for us to think about the characterization of percent body weight loss and just how much of that <unk> loss is actual muscle and the fact that we don't see that so I think these data.
Speaker Change: Clinically are highly encouraging and will be.
Speaker Change: Be generating that data second half that will be encouraging in terms of the program's future.
Speaker Change: Wonderful. Thank you so much.
Speaker Change: Thank you.
Speaker Change: Yeah.
Speaker Change: Thank you.
Speaker Change: We had the next version of the line of Ryan <unk> from Raymond James. Please go ahead.
Speaker Change: Hi.
Speaker Change: This is Anthony on for Ryan. Thank you for taking our call I wanted to ask what specific Biomarkers are you planning to report for this readout from our enlighten.
Speaker Change: For our wave zero three.
Speaker Change: Yes, I mean, the disclose Biomarkers in addition to obviously body weight.
Speaker Change: B activity. So that's the disclosed biomarker that we've reported there are others exploratory endpoints that we are looking at that we haven't disclosed but activity will be important and that will give us a sense of as Eric shared with elevation in BMI you see an increase in activity and so being able to follow those activity levels are going to give us a sense of target engagement. There also.
Speaker Change: Been informed that the last question and ability to follow these patients out over time and look at the durability of effect. So active and he will be an important biomarker to look like look at.
Speaker Change: And we will have additional biomarkers that will be evaluating in an exploratory fashion as part of the study.
Speaker Change: Alright, Thank you very much.
Speaker Change: Thank you.
Speaker Change: The next question a line of and then Douglas from H C. Wainwright and company. Please go ahead.
Speaker Change: Yeah, Hi, Thank you two questions from me. The first one is you don't have a lot of GNP one discussion.
Speaker Change: Revolves around appropriate fixed so was wondering what does the fundamental balance he talks about it.
Speaker Change: The pure trophic effect, so fleet loss.
Speaker Change: In terms of the signaling pathway at the second question is I wanted to understand your thoughts on the Saudi Sudan, and how does it differentiate.
Speaker Change: With with your program. Thanks.
Can you add some of that could you just repeat the last portion of the question. Yes. So the second one is with respect to fuzzy Sudan and your ATT.
Speaker Change: AT&T program differentiation in terms of what you have learned from the Pfizer data.
Speaker Change: I'll take the first one on your play are trophic effect that will come back to the second one just to think about whether or not we hear that one correctly.
Speaker Change: On the first side of it we think about the impact of to hit.
Speaker Change: And have any biology, I think what's intriguing and we saw that.
Speaker Change: Our preclinical data you would see it on human genetics and as Eric said, we even see a prospectively and looking with patients with elevated BMI is that activity is a hepatic I'm that's supportive of sustaining.
Speaker Change: At the sites and so actually the biology is very well correlated in fact the.
Speaker Change: The receptor for active and needs of the inhibiting the receptor and the ligand both feature very prominently on the genetics. So therefore, it's just important that the biology is theres a good concordance in biology between those.
Speaker Change: That both the target ligand in the receptor and so we saw that play out in the DIY mouth model across several opportunities again single dose.
Speaker Change: Against <unk> ones in combination with <unk> that showed its orthogonal in terms of its mechanism of action and then ultimately in sustaining and maintenance of weight loss. So again theres a good concordance between those two activities.
Speaker Change: Joe maybe just add today. So so so the ligand receptor pairs very specific in this case. So we don't expect any payoffs or pay it all our primary payout could be now obviously, we would expect downstream positive effects, so targeting <unk> seven so increase.
Speaker Change: Increasing life policies will lead to a lot of downstream paucity of metabolic effects, but thats not accountability, yeah and in terms of that I mean, just to beat to be really clear on minimizing any other player trophic effect outside as we're targeting the liver with actually Theres a high degree of specificity.
Speaker Change: <unk> inhibitors and Theres a lot of other active and so sometimes people get confused so maybe that's a stepping back there are a variety of different activities in the family. Hence the good reason to targets that law again, not the receptor the concordance of activity as it is produced in the hepatocytes with its the receptor on the appetite. So one it's an ideal target for us.
Speaker Change: Sorry, RNA in the liver and then you put <unk> on that and again you drive specificity to that single cell type anyway. So we're not worried about off target effects of that particular activin receptor.
Speaker Change: Then you were asking just to make sure I have it because that was a little bit with.
Speaker Change: So literally in their own right.
Speaker Change: That's right.
Speaker Change: Yeah, Yeah, sorry, yeah, yeah, yeah. So I mean, if we think about.
Speaker Change: <unk> and the reason why we've got really potent durable <unk> why why did we didn't take a gallon neck potent SA RNA forward in Alpha one antitrypsin deficiency is the recognition that actually potency as it could be potentially detriment that the protein that you need. So therefore, it just turn off that protein Ulta.
Speaker Change: <unk>, while it may clear hepatic aggregates, because you no longer are producing misfolded protein you ultimately put patients on a course for IV protein replacement therapy right you prevent the protection of the lung and so therefore this is the benefit of multi modal platforms as we could step back and actually say, even though we could it's not the best tool to do that job EDA.
Speaker Change: <unk> is the best tool to do that job, where you create a functional protein and therefore restore function to protecting the lung, but also allow the removal of aggregates from the liver. So again the opportunity that we have with different tools is and despite a potentially best in class SA RNA format, we wouldnt apply rsi RNA format to that but we do see in terms.
Speaker Change: The differentiation of <unk> and we shared this again and they are paper highly potent highly durable SA RNA formats, not just in <unk> in the liver, but in CNS and other tissues as well.
Speaker Change: Got it thank you.
Speaker Change: Yes. Thank you.
Speaker Change: Thank you.
Speaker Change: We have the next to the line of Luke see from RBC. Please go ahead.
Speaker Change: Oh, great. Thanks, so much for taking our questions. This is Lisa on for Luka.
Speaker Change: Maybe a couple here on <unk>.
Speaker Change: The <unk> T program makes progress.
Speaker Change: Wondering if you can share what you need to see before.
Speaker Change: Starting a phase two.
Speaker Change: You know what the bogey to achieving <unk> CRM above 11, or do you need to see something closer to 20 micro molar, which is more in the normal range.
Speaker Change: Any color here would be helpful.
Speaker Change: Yes, I mean I think the goal is that we'll complete this study and that will obviously guide the framework and planning of the phase II I mean were already at 11 micro molar single lowest dose. So the opportunity we have with more doses of more frequency. It's really two things one is pushing that dynamic range. As you said between 11 and 20 and really thing not just in total.
Speaker Change: What dynamic range do we get to within EM edited protein. So that's one big opportunity the second.
Speaker Change: As many of you are aware what do you want to do in this phase one two study is really defined not just a potency aspect, but the durability. So we will be able to do both understanding of dosing frequency and target product profile in terms of alpha one antitrypsin levels and that'll be determined at the end of the study as we plan forward into the phase II.
Speaker Change: Hi.
Speaker Change: Paul maybe one on on the regulatory path here.
Speaker Change: Yes.
Speaker Change: How are you thinking about a path to approval for <unk>.
Speaker Change:
Speaker Change: Will you potentially need to run a head to head study versus and <unk> as long acting on augmentation therapies.
Speaker Change: Should it be fully approved by the time you already see that pivotal study.
Speaker Change: Color here on your thinking about regulatory it would be helpful.
Speaker Change: Yes, I mean this is the wonderful aspect of being partnered that as the studies potentially could become more complex. Although we do believe there is still a pathway for approval based on if you can if alpha one antitrypsin levels right in human levels and healthy protein is differentiated and it's still driving a therapeutic threshold for approval.
Speaker Change: Then that should still support an accelerated pathway has a different approach than IV protein replacement, so editing versus protein replacement should be a potential pathway I think the opportunity that we have discussed two and our partner will be thinking a lot about that is.
Speaker Change: Being able to drive continued ways of differentiating this program and as well as driving.
Speaker Change: Opportunities for expansion, if we think about <unk> in total and why we're incredibly excited about the data we'll have this year and what it's going to inform going forward.
Speaker Change: There is a belief that there is a number of COPD patients who are.
Speaker Change: Technically being called non responders, who may actually be alpha one antitrypsin patient. So I think the opportunity ahead to think about again as youre pointing out respiratory endpoints pathways in the regulatory environment I think still speak to the fact that there is a regulatory approach that's driven off of the numerical threshold in terms of its delivery, but not to be forgotten.
Speaker Change: Is the hepatic endpoints and I think there is the opportunity to bifurcate into subsequent studies those patients who have liver disease, and how do you build liver and lung ultimately into a combined label so not a TD patients arent lung patients or liver patients <unk> patients and they have both lung and liver disease, and so I think the opportunity.
Speaker Change: <unk> ahead is really not to just think about it as a treatment for lung disease, but really have treatment of ADHD and I think our partner and we are both excited about what that opportunity provides.
Speaker Change: Got it thanks for taking our questions.
Speaker Change: Thank you.
Speaker Change: Thank you.
Speaker Change: We have the last question from the line of Medicine from B Riley. Please go ahead.
Speaker Change: Hey, Thanks for taking our question.
Speaker Change: So with the 200 Meg single dose.
Speaker Change: <unk> already seen that.
Speaker Change: T conversion is over 60%.
Speaker Change: Do you believe or are you confident that the 200 Meg.
Speaker Change: <unk> multi dose and or the 400 gig.
Speaker Change: Single dose could push that conversion rate to over 80%.
Speaker Change: And any feedback site specific feedback youre getting regarding enrollment and then a follow up.
Speaker Change: Yes, I think on the last one enrollment is going very well, particularly after we had our last datasets. So our conversations with Kols we're achieving.
Speaker Change: Or is I guess levels after the lowest single dose with highly encouraging along with the profile.
Speaker Change: I do think if we think about both the opportunity and actually why the 200 milligram multi dose is so important is if you think about the total amount of drug under the 200 milligram dosing. There is a lot of we're going to get a lot of doses a lot of medicines into the cells and a lot of opportunity to see how that ultimately pushes the upper balance of edit.
Speaker Change: The 400, the single dose right. So we're going to get a good sense of dose response between and see going forward 200 versus 400 on the single dose basis, where you can plot out some of the pharmacokinetics, but the 200 multi dose is going to be extraordinarily informative and it's why we're excited.
Speaker Change: Before that data this year.
Speaker Change: Got it understood.
Speaker Change: And then I also wanted to ask you you've mentioned ret syndrome today in a couple of times as a potential indication that would be appropriate for opening editors.
Speaker Change: Have you discussed how you would get across the blood brain barrier is this something related to your European or your stereo chemistry.
Speaker Change: Or would you need to.
Speaker Change: The.
Speaker Change: Shuttle vehicle.
Speaker Change: Yes.
Speaker Change: So just to step back PCB too I think we've got a variety of opportunities if we shared well beyond CF <unk> <unk> others.
Speaker Change: Others right. So we've we've shared a whole range importantly, <unk> important to your point as we're really defining what CNS editing looks like both from an interest equal standpoint, and as you mentioned and we're going to have opportunities as we think about research day. Later this year to think about alternative approaches that we're doing to for delivery and so we've spent a lot of effort in.
Speaker Change: Looking at how we deliver and this is not just unique for Amyris, how we think about <unk>, how we think about our amer technology, but being able to think about accessibility. So theres more to come as we think about the platform approaches as we get into research day second half of this year.
Speaker Change: But we spend a lot of time thinking about alternative ways of delivering across the blood brain barrier.
Speaker Change: Okay.
Speaker Change: Got it.
Speaker Change: Helpful. And then my last question is have you said, how many points you would enroll and the expanded open label cohort in 531 trial and then at what point you would reengage with the FDA thinks.
Speaker Change: Yes, so being engagements around the 48 week data and our plan for confirmatory, we had as we said earlier the alignment on what's required for filing.
Speaker Change: To talk about numbers, we said the extension cohorts Thats. The 11 boys continuing our monthly plus the additional expansion cohort that we would expect to be in line with other exon 53 files like El Paso.
Speaker Change: Would all be supportive of the NDA filing in 2020 and that would be the next update as well on a pilot.
Speaker Change: Yeah.
Speaker Change: Thanks to the progress.
Speaker Change: Thank you.
Speaker Change: Yes.
Speaker Change: Thank you.
Speaker Change: That concludes our question answer session I would like to turn the conference over to Dr. Paul <unk> for closing comments.
Speaker Change: Thank you for joining our call. This morning, we look forward to connecting with many of you at upcoming conferences have a great day.
Speaker Change: Thank you.
Speaker Change: The conference has now concluded. Thank you for attending today's presentation you may now disconnect.
Speaker Change: [music].