Assembly Biosciences, Inc. (ASMB) Earnings Call Transcript & Summary

Good afternoon. And welcome to the Assembly Biosciences' HBV Portfolio Progress Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to hand the call over to Amy Figueroa, Interim Investor Relations Consultant for Assembly. Please go ahead.

Good afternoon. And thank you for joining us as we discuss the recent progress with Assembly's portfolio of clinical stage core inhibitors, which are advancing in development for the treatment of patients with chronic hepatitis B infection. This afternoon, we issued a press release reporting our financial results for the first quarter of 2020 and providing a corporate update. This press release and the slides we will refer to during the call are available in the News and Events section of our corporate website at www.assemblybio.com. After our prepared remarks, a PDF of the slides will be available from our website. Also, a replay of today's call and webcast will be available from our website. In a moment, I will turn the call over to Dr. John McHutchison, Assembly Bio's Chief Executive Officer and President, to provide a corporate update and the virologic response criteria or stopping criteria, which will be used to determine which patients begin coming off of therapy in Study 211 later this year. Then Dr. Luisa Stamm, Chief Medical Officer, will review the criteria in more detail and provide an overview of the abstracts accepted for presentation at the virtual EASL meeting August 27 through 29, including data on our lead core inhibitor 731, second-generation core inhibitor 2158 and our highly sensitive assays. Finally, John, Luisa, Dr. Richard Colonno, our Executive Vice President and Chief Scientific Officer of Virology; and Tom Russo, our Chief Financial Officer, will be available for the Q&A portion of the call. Before we begin, I want to remind you that we will be making forward-looking statements, including statements regarding our future research and development plans, evaluation of interim data, the timing of clinical trials, trial results and therapeutic potential of our development programs. These statements are subject to the safe harbor protections provided under the Private Securities Litigation Reform Act of 1995. They involve certain assumptions, risks and uncertainties that are beyond our control, and actual results may differ materially from these forward-looking statements. A description of these risks can be found in Slide 3 as well as our latest SEC disclosure documents and press releases. Assembly does not undertake any obligation to update any forward-looking statements made during this call. I'll now hand the call over to Assembly's CEO, Dr. John McHutchison.

Thanks, Amy, and welcome to everyone on the call today. I'm pleased to be speaking with you all again. Whilst we had planned to be doing this in person at EASL in London a few weeks ago, we're happy to now provide you a broader corporate update coinciding with the end of the quarter, along with some other important updates as Amy has already outlined for you. In these uncertain and unpredictable times, we at Assembly remain focused. We have continued our operations thus far as permitted during the shelter-in-place orders. We have rapidly adapted our operations, of course, and we continue to regularly assess the situation. The FDA provided guidance in March that enabled us to monitor patients in our studies in their homes, including virtual visits, laboratory testing and study products shipped directly to trial participants. As a result, we have been able to mitigate, to the extent possible, any potential impact to Study 211. For future studies, we are working to expand the geographic diversity of sites and bringing on countries first that are past the peak of the corona virus outbreaks such as China. To date, our current and future plan trials have not been subject to any significant impact. Importantly, we have also had the financial resources needed to advance our programs following the completion of our offering this past December, and we continue to expect our current cash of $249 million as of March 31 to fund our operations into 2022. Over the past year, we have continued to further recruit talented experienced leaders to Assembly, including our Chief Financial Officer, Tom Russo; and our Chief Medical Officer, Dr. Luisa Stamm, during the fourth quarter. More recently, we have welcomed Jason Okazaki as our new Chief Legal and Business Officer. Jason comes to us with an extraordinary depth of both legal and M&A and licensing expertise. Carl Enell has joined us to work closely with Jason, Tom and myself to head corporate development. As we do more internally and externally in terms of partnerships, collaborations and other activities to grow our portfolio, both Jason and Carl will be critical to the success of the organization. Additionally, Michele Anderson joined us to lead the regulatory group. Michele has deep experience across multiple therapeutic areas with numerous product approvals in many geographies. These skills will put us in good standing as our programs advance globally. Now turning to Slide 5 on the R&D side of the organization, we continue to execute. I'm pleased with our pipeline progress and our acceleration of activities within the last 6 months. As it relates to hepatitis B, our focus for today's call, we have submitted an end-of-Phase II meeting request and briefing document to the Chinese regulatory authorities for 731, our lead hepatitis B core inhibitor to discuss with them what a regional program for that drug might look like. We look forward to those interactions, and after, we'll be able to speak more about the timing and components of that program, initially as a chronic suppressive therapy that we aim to link to a subsequent finite duration regimen which is our ultimate goal. Lastly, we have now also finalized the stopping criteria for the 731 Phase II program, and we'll outline those details and their implications today. Also, we'll provide you a high-level overview of our abstracts accepted for EASL, whilst preserving more detailed scientific findings for those 4 presentations when they actually occur in August. In addition to the progress of 731, we're advancing to more potent second-generation HBV core inhibitors into clinical development or in clinical development. 2158 has completed Phase Ib dose-ranging cohorts and remains on track to start a Phase II proof-of-concept trial in the second quarter, that is this quarter. Luisa will touch upon the final top line data from those cohorts and share the Phase II trial design later. Also for 3733, we have opened the first-in-human Phase I study in healthy volunteers to evaluate that drug's safety, tolerability and pharmacokinetics. Let's move on to the updates in our ongoing Phase II program for 731 and the stopping criteria we've defined. To recap the trial design shown on Slide 6, a broad range of patients with chronic hepatitis B infection were enrolled, included with E antigen negative or positive patients who were previously receiving suppressive Nuc therapy. That are randomized in Study 201 to receive 24 weeks of therapy with the core inhibitor 731 or matching placebo for a duration of 24 weeks. Also, as shown in the bottom row, another group of naive-to-treatment E antigen-positive patients were similarly randomized. After the first 24 weeks, all patients were then offered open-label extension trial enrollment in Study 211, where they all received the combination of Nuc and the core inhibitor 731 for an additional period of 1 year. Of the 92 patients entering the open-label extension, 84 currently remain in the study and have reached or are approaching the 76-week treatment time point. Next, as patients have progressed through Study 211, we have previously reported the proportions with progressive reductions in viral antigens and also the proportions with HBV DNA and pregenomic RNA, lower thresholds of our in-house sensitive assays. As many of you know, pgRNA has only 1 source within an HBV-infected cell, the mini chromosome, cccDNA. Our data to date have, therefore, directly and indirectly indicated prolonged and deep viral suppression are necessary, of course, to prevent relapse after any potential finite-duration therapy. Now that patients in this open-label extension study are approaching the 52 to 76 weeks of treatments of the combination, our next step has been to determine which patients should cease therapy. Our hypothesis has been that with a period of prolonged viral suppression to levels below our most sensitive means of quantifying any evidence of viral replication, we have also blocked the replenishment of cccDNA and depleted that pool, which should allow therapy to be withdrawn without evidence of a viral relapse, with a drug that has continued to show a favorable and differentiated safety profile. Thus, we can evaluate patients off therapy and determine if they achieved a sustained virologic response, or SVR, as we coined the term initially for patients with hepatitis C. After careful internal consideration, discussions with investigators and lastly, with agreement with the FDA, we've arrived at those criteria. Slide 8 sets forth the stopping criteria, as measured using our newest and most sensitive assay for detecting any evidence of residual viral replication. We defined the lower threshold for this assay as total HBV nucleic acids, that's DNA and pgRNA combined, less than 20 IUs per ml, and we'll provide more detail on this assay later in the presentation. Patients will be eligible to cease therapy if they have had no evidence of quantifiable viral replication using this assay for 7 consecutive monthly visits at treatment week 76. We chose this 6-month period of negativity as it's consistent with the half-life of cccDNA as we recently published in Hepatology. For patients who are E antigen positive, the detectable levels of E antigen must also have been 5 IUs per ml or less on each of those 7 visits also. After cessation of combination therapy, the next critical part of this experiment will be to closely monitor the patients and carefully document the presence or absence of a sustained virologic response. Recall that historically, fewer than 5% of patients with chronic hepatitis B achieved sustained suppression of viral markers of replication after ceasing treatment or SVR. We plan to monitor patients monthly for safety, and we'll measure ALT values, standard virologic markers and we'll apply our sensitive DNA and pgRNA assays as well. For patients that reached the 6-month time point without relapse and achieve SVR 24, as highlighted in the middle of the slide, we'll continue to monitor them less frequently through a total follow-up period of 3 years, similar to what we also did with hepatitis C patients when we were initially monitoring for SVR and its durability. Those who do relapse will be detected early with our sensitive assays. And of course, standard-of-care Nuc therapy will be reinitiated as is clinically indicated. So for patients in the current trial, how will this play out? As shown at the top of the Slide 10, that is those patients that achieve these stopping criteria will stop both 731 and the Nuc therapy at treatment week 76, and we'll continue to monitor them for SVR as we've outlined today. For those patients shown in the middle of the slide who did not meet the stopping criteria and have, therefore, had an insufficient or inadequate biologic response, we will discontinue 731 but continue their Nuc therapy, and they will eventually complete the study. And for those patients shown at the bottom, we started in the naive patient cohort with the highest levels of DNA and pgRNA and who have been responding to date with an initial virologic response, which we have defined as decline in pgRNA from baseline of at least 2.5 logs, we'll be extending their duration on the combination therapy to provide them the opportunity to satisfy the stopping criteria that we have outlined today for the other groups. For more details now and a discussion of what we have planned for EASL also, I shall hand the call over to our Chief Medical Officer, Luisa Stamm.

Thank you, John. I'll follow on where you left off and walk through the treatment decisions for each patient population in Study 211. I'll speak first on Slide 11 to the virologically suppressed E antigen-negative patients who entered Study 201. These patients have been receiving NrtI for a number of years and therefore, had very low levels of HBV DNA and pgRNA at the time of entry into the study. All of the patients who continue on treatment have met the virologic response criteria, and therefore, at treatment week 76, all these patients will discontinue both 731 and NrtI. They will then be monitored closely for safety and SVR, as John described. The next group is shown on Slide 12, the virologically suppressed E antigen-positive patients who entered Study 201. A proportion of these patients will meet the stopping criteria. And at week 76, they will discontinue both 731 and NrtI and be monitored for SVR for up to 3 years. Those patients who do not meet the criteria will discontinue 731, but they will continue standard-of-care NrtI therapy. They will be monitored for 12 weeks, then complete the study. Finally, on Slide 13, we are showing the treatment-naive group of patients, all of whom were E antigen positive at enrollment into Study 202. For these patients, who were initially untreated and started the study with high levels of DNA and pgRNA, we are first evaluating the initial virologic response to determine who will continue treatment of 731 and NrtI. Specifically, patients who have had at least a 2.5 log decline in pgRNA at treatment week 76 will continue to receive the combination treatment with 731 and NrtI, extending for up to an additional 48 weeks. During this treatment extension, we'll continue to monitor patients who are responding, and we will stop 731 and NrtI when they meet the same stopping criteria that we have outlined for the other groups in the prior slide. Patients with insufficient virologic response will discontinue 731 and continue on NrtI for 12 weeks. As we prepare to roll out these treatment decisions, the projected flow of patients in the 3 groups is shown on Slide 14. It's important to remember that not all patients have reached 76 weeks of treatment yet. And these figures include our projections based on the currently available data. The proportion shown represent the number of patients enrolled in Study 211. There are some patients who have discontinued 731 already for other reasons, most commonly withdrawal of consent. These are shown in the light gray on the right. First, for the virologically suppressed E antigen-negative patients, approximately 90% are projected to meet the stopping criteria and will discontinue 731 and NrtI after 12 or 18 months of the combination regimen. Next, almost half of the virologically suppressed E antigen-positive patients are projected to meet the staffing criteria and discontinue both 731 and NrtI. Lastly, for the treatment-naive E antigen-positive patients, the majority or approximately 80% are projected to achieve an initial virologic response and will have their treatment with both 731 and NrtI extended to provide them an opportunity to achieve the same stopping criteria as outlined for the other groups. As John mentioned at the outset, we developed these criteria after careful deliberation. We are now excited about moving the study to the next phase and looking forward to the important data that it will generate. Moving on to EASL, we are very pleased to have 4 presentations accepted, as shown on Slide 15, one as an oral and 3 as a poster with 2 of these being late breakers. We expect the complete abstracts will be available online about a week before the conference, which is now scheduled to take place virtually in late August. There are 2 presentations on Study 211, one on our highly sensitive assay and one on the dose-ranging cohorts from the Phase Ib study with 2158, our second-generation core inhibitor. On the next few slides, I'll provide a high-level overview of what we plan to cover in these presentations. I'll begin first with our highly sensitive HBV DNA and pgRNA assays on Slide 16. These were developed by the in-house scientists at Assembly to monitor key viral markers in our clinical studies. The left section of the slide compares Assembly's assay to the commonly used cobas assay. We used cobas in Study 202 for measuring DNA levels in treatment-naive patients. However, for virologically suppressed patients in 201, who had already reached the lower limit of quantification or LLOQ of the cobas assaying, DNA was measured by Assembly's quantitative PCR gel assay. This assay's limited detection of 5 IU per ml allows for improved accuracy, enabling measurement of deeper viral inhibition in these patients. The center of the slide shows our improvement in measuring pgRNA. For comparison, the DDL assay measures all HBV RNA, not just pgRNA, with an LLOQ of 11,000 copies per ml. The Assembly assays more specifically measured pgRNA and also have improved sensitivity with LLOQs of 800 and 200 copies per ml using the treatment-naive patients in Study 202 and the virologically suppressed patients in Study 201, respectively. For your reference, we previously referred to the LLOQs in these assays as 135 units per ml in Study 202 and 35 units per ml in Study 201. On the right, you'll see our latest highly sensitive assay, which is the one we will be using in the stopping criteria for Study 211. This simpler composite assay measures total HBV nucleic acids, both pgRNA and DNA. It has a quantitative readout with LLOQ of 20 IUs per ml, more sensitive than our prior quantitative assays. Next, I'll review the updated data from Study 211 using these new, more sensitive assays. On Slide 17, you'll see an update on the virologically suppressed E antigen patients from Study 201/211. The proportions of these patients whose HBV DNA is not detectable by the sensitive assay with the 5 IUs per ml limit of detection is shown on the left. As we presented at AASLD last year, at baseline, a small proportion of these patients had undetectable HBV DNA, shown in light gray. With the addition of 731, this proportion increases to over 70%, shown in light and dark blue. We are pleased to see that with longer durations of combination therapy, we have continued improved deeper viral suppression of viral replication. On the right side is the data with the new composite, DNA and pgRNA assay, which has been incorporated into Study 211 from week 24 of treatment onwards. For patients shown in gray, who initially received placebo and NrtI through the first 24 weeks of treatment, you can see a light -- in light blue a far greater proportion with DNA and pgRNA less than LLOQ after addition of NrtI -- after addition of 731 to NrtI. For the patients who received 731 and NrtI throughout the study, shown in dark blue, received a proportion after 24 weeks of combination treatment with similar, and this continues to increase further over the next 24 weeks and after. Recall from earlier in this presentation that about half of these patients are now projected to meet the stopping criteria and discontinue both drugs at week 76 because they also had E antigen less than 5 IU per ml. For the treatment-naive E antigen-positive patients from Study 202 and 211, not included here, we have planned to do a data cut in late June and provide a detailed update in August at EASL. To remind you, this group started with the highest levels of DNA and pgRNA. And overall, they are continuing to progress with approximately 80% meeting the initial virologic response criteria. These patients are responding, and we are extending their therapy. Now let me turn to Slide 18, and the data from the virologically suppressed E antigen-negative patients, a population which we will present in detail for the first time at EASL. Of note, these patients enrolled in Study 201 after prolonged NrtI treatment with a mean duration of 4 years. Also, most, 88%, had E antigen seroconverted and had detectable anti-HBE antibodies. So it's not surprising that at baseline a high proportion of these subjects had already achieved undetectable HBV DNA, reflective of deeper level of viral suppression compared to the E antigen-positive population on the prior slide. Even with this, we see on the left, deeper suppression during treatment with 731, as measured by our sensitive DNA assay, with increasing proportions of patients in both groups achieving undetectable DNA with longer-duration combination therapy. On the right side are the data with the composite DNA and pgRNA assay. All patients in this population consistently have had DNA and pgRNA less than 20 IU per ml. Recall from earlier in the presentation that these patients have all met the stopping criteria for at least 6 months. And therefore, all will discontinue 731 and NrtI after 12 or 18 months of combination therapy and will be observed for SVR. Now let's move to cover 2158. Our second-generation, more potent core inhibitor and the data from the completed Phase Ib dose-ranging cohorts that will be presented at EASL. In this study, E antigen-positive patients received 14 days of placebo or 2158 at the once daily dose of 100, 300 or 500 milligrams. Across the cohorts, 2158 was well tolerated and demonstrated potent antiviral activity. With the 300-milligram dose, the decline from baseline on day 15 for HBV DNA was 2.5 logs and for pgRNA was 2.2 logs. Based on this data and the less than dose proportional increases in the pharmacokinetic parameters, as shown in the table, the 300-milligram daily dose has been selected for the upcoming Phase II trial, design of which is shown on Slide 20. This trial, which is expected to initiate this quarter, will enroll treatment-naive patients with E antigen-positive chronic hepatitis B without cirrhosis. 80 patients will be randomized 3:1 to receive 2158, 300 milligrams or placebo and entecavir once daily for 72 weeks. The objective of this proof-of-concept study is to evaluate the safety and efficacy of longer-duration treatment with this combination. The endpoints of this study include safety and changes from baseline in HBV DNA, pgRNA, along with viral antigen. The data will be used to indirectly compare our first and second-generation core inhibitors in terms of their efficacy to prevent the generation of new cccDNA. I'll now turn the call back over to John.

So thanks, Luisa. Before we open the Q&A session, I'd like to recognize how fortunate we are to be in a strong position now. We've now put into place an experienced team. We raised the resources to be well capitalized. And we remain on track to execute on our plans. Looking ahead into the rest of this year, as shown on Slide 21, we have several important milestones we anticipate in the coming months. These include, as shown, the start of our Phase II proof-of-concept clinical trial for 2158 this quarter that Luisa has just outlined. Also, the first preclinical data from our immuno-oncology microbiome program that'll be presented virtually at this month -- next month's AACR; 4 presentations that you heard about today relating to our hepatitis B portfolio at EASL in late August; our ongoing regulatory interactions in China and the U.S. as we aim to initiate studies to enable registration; and of course, we continue to evaluate potential partnership opportunities in China that might help us move this along. And importantly, beginning to take patients off therapy in Study 211 later this year to monitor patients for sustained viral response, as Luisa has outlined for you today. So we are now happy to take your questions. Operator, you may now start the Q&A session.

[Operator Instructions] Your first question comes from the line of Brian Skorney from Baird.

Congrats on getting the go-ahead on moving forward with the stopping criteria. I guess maybe just kind of high level. I know we don't have a lot of historical data on patients who achieve, curious, a lot of it's still kind of guesswork. But when you kind of consider the 3 buckets of patients, the naive, Nuc-suppressed E-positive and Nuc-suppressed E-negative patients, is there anything to kind of take away from the historical characteristics and anything you think is a more likely cohort to achieve -- carry another treatment-naive sort of a -- likely a blinded hybrid of the Nuc-suppressed E antigen positive and E antigen negatives. Any sort of theoretical reasons why one should be more likely to achieve functional cure than the other?

Brian, thank you for your comments about getting clearance and approval from everybody, our investigators and the regulators and internally for us to move forward with the stopping criteria. We've thought a lot about them. Look, it's a fantastic question, which group are most likely to be cured. And you're always looking back historically at very low rates of sustained viral suppression off therapy, not cure, in patients who were treated with interferon or a Nuc, and it's 1% to 5%. Now the rates are higher. If you look at E negative, people have been suppressed, for patients on Nucs for a long period of time, many, many years, and a lot of that data comes from China. And in those that have reductions in other viral antigens, such as E antigen, and now we're looking at pgRNA, which has really not been influenced in the short term in any way, shape or form by our prior Nuc-based therapies. So we don't know the answer to your question. It's part of the experiment we're doing. I believe that the E antigen-negative patients have started low and been suppressed for a long time. We know, as Luisa said to you today, we have suppressed both DNA and pgRNA with our sensitive assays for many months, and we'll see how they go. Obviously, it's going to take longer for the naive patients who started much higher. So it's the experiment we're doing. We're not exactly sure what the answer is biologically. I think the E-negative patients might have the best chance. Look, whatever it is, whatever group it is, the important point is, as I've said before, that anything that's at least 10% better than standard of care, which is 1% to 5%, respectively, for the 2 approved therapies is something that is important for patients and important for doctors to tell their patients and will change prescribing patterns. So if we get around 15% across the board here, I'll be happy about that. So a longer answer, but I hope I've given you our thought process and the science around this. Thanks for your question.

Your next question comes from the line of Geoffrey Porges from SVB Leerink.

This is Brad Canino on for Geoff today. And congratulations as well on achieving all of this and really staying on track during these difficult times. And I'd like to ask, again, on this E-positive virally suppressed population. You're saying you're going to discontinue 42% of them because they didn't achieve the responses you wanted. But you're willing to extend treatment further in the treatment-naive population. So why would you not be extending treatment for the E-positive patients?

Brad, it's John to start, and then I'll hand it over to Luisa. I think your question was related to the E-positive suppressed patients, that have some small amount of E antigen left, why aren't we continuing them on? So I'll let -- we've talked about that a lot, and I will let Luisa answer it. Thanks for your nice comments about staying on track and being able to do all that during the events over the last few months. So Luisa, some comments and clarity around why we chose the cutoff of 5 international units of E and perhaps a little bit more data.

Sure. Thank you, Jeff, for the question. I think first, to what John just mentioned, the cutoff of 5 IUs per ml for the discontinuation of treatment in the E antigen virologically suppressed population. As you know, there's no accepted cutoff for what's low and meaningful with regard to E antigen and predicting SVR for patients receiving treatment with a core inhibitor and NrtI. What I can tell you is that the 21 E antigen-positive patients who are less than 5 and predicted to stop treatment, 2/3 are less than 1, and all but 1 are less than 3. So we're really conducting this experiment in a broader population to access -- to assess the importance of an absolute change in E antigen. This will maximize our learning about the contribution of 731 to NrtI. And then moving forward, we'll take the results and refine our criteria for future study. I think part of your question, if I understand it correctly, is also why would we discontinue those who are -- why will we continue NrtI and discontinue 731 in the other patients in the cohort. And this really reflects the maturity of the data now and where we are in this open-label extension, where most patients have already received or all patients will have received 12 or 18 months of therapy. So we think this is a reasonable amount of time to assess the impact of core inhibitor on top of standard-of-care NrtI.

So Brad, it's John again. Just one other point. Two other points I'd like to make is a lot of these patients are trickling along with very, very, very low levels of E for a long period of time. And it raises this issue of what does that mean? And we'll do this experiment, and we'll find out what it means, but the majority are very, very low, as Luisa described, whether that comes from an integrant or not, we don't know. There's great debate, as Rich has talked to you many times before about whether E integrants are relevant and important. We'll do that experiment now. Look, the other thing about the naives, I'd just like to mention and pick up to you is they started with such high levels of RNA and DNA, they're at least a year behind all of these other patients. So that's why they're continuing on. And as Luisa said, we'll do this experiment in the E -- E positive suppressed now.

Your next question comes from the line of Michael Yee from Jefferies.

John, hope you can hear me okay. A couple of quick ones. A lot of information there. So thanks for all that new disclosure. Question one, I think I heard you right or saw that 49% of people met the stopping criteria in E positive, obviously, which is huge new information. When are you actually going to take patients off? And then when would you report how many do or don't rebound? Are you going to wait 6 months after that? So maybe describe the timing when we would get that huge answer. Question two, on the second-generation one, are you going to implement the stopping criteria there too? Or you're just going to try and see if you can get higher than 49%, who meet the stopping criteria? I guess that would be the goal of that study. And then question three, on the China study, is that potentially for an FDA submission by running that or a China submission? Maybe just clarify that.

Thanks, Mike. We heard your 3 questions. So the first question is, when are we going to stop taking people off therapy, and when we're going to report it. So let's work through this one by one. Luisa, so when will we start taking people off therapy?

Yes. So as we mentioned on that slide, Michael, it's a projection right now. I can say that as of last week, about 1/3 of individuals on the study have reached treatment week 76. So we plan to start taking people off of treatment by June.

And then in terms, Mike, of -- the second part of that first question, in terms of -- in terms of when we're going to report this, the answer is, when we're sure we have the right answer, which is not meant to be cryptic, but there's 2 major factors. It's having a significant number of patients where you feel it's a real representation of the cohort. And then it's having the 6-month follow-up in that cohort. So it's really both of those factors. Look, we could report that at a scientific meeting. We could report it -- it's material to us. We could report it as a press release separate from the scientific meeting. Some of you have felt that it might be at AASLD later this year. That's a real stretch, and I'd be thinking about this into next year for all of you. I think that would be the right way to think about it. Will we implement the stopping criteria for 2158 as we did? Yes, we might modify them if we learn from the stopping criteria. But by that stage, we plan on implementing the same. Luisa, a few words on that?

Yes. So the way the protocol is currently written, there are no stopping criteria. As I mentioned, what we'll do is take the results from the 731 study, refine the stopping criteria, and then we plan to amend the protocol and apply it to the 2158 program.

And Mike, the last question, just to finish up for you is the China submission and will that be part of a global submission. Too early to talk about all the details. We've submitted -- we have our plan. We have submitted our end-of-Phase II request for a meeting in China. As you know, these things have to be discussed and negotiated and eked out in greater detail. We'll present all of those findings once we have it sort of tied down, but it'll be like most other Phase III programs, 2 studies. Maybe they'll be the same. Maybe there'll be different populations. As I said today, finite, potentially bridging to -- suppressive therapy, subsequently bridging to finite. So -- and whether we use that data for global submission, that would ideally be our goal. So thanks for your 3 questions.

Your next question comes from the line of Salim Syed from Mizuho.

Couple for me. On -- just a high-level one here. On the -- your discussions with the FDA, and I presume other KOLs, it seems like from the slides, obviously, it's largely focused on pgRNA versus the -- what people historically have focused on S antigen. Have you sensed this shift at all at the FDA or amongst your KOL discussions, people taking focus off S antigen and focusing more on pgRNA as the right marker? That's question one. And then the second question was just on Slide 9, it looks like from the patient follow-ups for -- after year 1, it'll be every 3 months. I just want to make sure I'm interpreting that correctly.

So I don't want to speak about shift in terms of FDA really, Salim, or what they're thinking. I think we are seeing in the scientific community a shift. And listen, I think, it might be a good opportunity to have Rich talk about the assays and how they've evolved over time and how they're somewhat reliant and importantly, reliant on pgRNA, and then I'll follow-up with the second part of the question. So Rich, you haven't had an opportunity to talk much about all this work you guys have done on these assays and why.

Yes. Sure. Thank you. And hi, everybody. Yes. So we quoted the shift, I think, not like just in the agencies but also investigators in terms of the importance of S antigen, especially given all the data that the vast majority of that comes from integrant, that's a scientific fact now. And especially as you go to E antigen-negative patients, it's close to 100%. So -- and that is the next criteria that one uses for success in monitoring patients on treatment as we're doing in this study, and that's where you see this shift now much more to sort of toward pgRNA. We're not totally there yet. It's still DNA to a great degree. But pgRNA is the primary marker of cccDNA. And everybody now scientifically, I think, does agree that, look, at the end of the day, to cure patients, you're going to have to get rid of cccDNA and pgRNA is the greatest marker for that. So our emphasis is on the pgRNA. We're one of the -- we're very happy to be one of the leaders in the scientific field on this, and developing the science behind that. And I think there's a lot of uptake now on a lot of different -- for a lot of different parts of the treatment world, that pgRNA is probably a very important element of this. And if you can get the DNA and pgRNA down to these very low undetectable levels, then you have checked 2 major boxes. You've stopped viral replication and you've depleted cccDNA. So anyway -- so that's what it is. So there's no definitive answer to it. There's no edit that's come down from the FDA or anybody else to say they're going to forget about S antigen. But I think there's clearly a trend now where everybody is moving in that direction.

Thanks, Rich. And fortunately, with our combination therapy, we've been driving both DNA and RNA -- and pgRNA down. So we've created these more and more sensitive assays to try and measure what was previously unmeasurable or below the level of detection. That's a testament to what the combination is doing, Virology 101. But look, the other thing I would say, Salim, before we get on to the second question, is just as -- in doing this internally, our lead investigators are completely on board with this conceptually. It's an important experiment that nobody has ever done before. If somebody had done it before, we wouldn't be discussing it, right? It would be -- everybody would know the outcome. So that's important. And the regulators have interacted with us and agreed upon this plan to go forward and monitor people when we take them off therapy. The other important point about this, where the FDA -- I can't speak for the FDA, but their guidance document clearly says there's 2 ways to a finite therapy. One is absence of HBV DNA for 6 months after stopping therapy using the cobas or the commercially available assay. That doesn't talk about surface antigen. That talks about the importance of controlling viral replication as measured by DNA. And then the second component of that is about surface antigen. So clearly, they recognize there's both of those. Long-winded answer to your question, but I think it's important information. And then, Luisa, if you could answer Salim's second question about the timing of follow-up after the first 24 weeks.

Sure. Thank you. As you referred to on Slide 9. We'll be looking very closely over the 3-year duration. We'll initially be looking monthly as indicated on the slide, and then we'll slowly be spacing those out. We appreciate this is a long study, and we'll be going first to 2 -- every 2 months and then finally in the last year to every 3 months. So that gives you a little bit of an idea about the cadence of our plans in terms of monitoring these individuals off of therapy.

Your next question comes from the line of Raju Prasad from William Blair.

Congrats on the alignment. Can you just provide a little more color on the assumptions that went into the 211 projections on, I think it's Slide 14. And then as far as 2158, just wanted to understand there's a treatment-naive E antigen-positive study. Do you plan on studying in E antigen negatives? And are the development of that programs going to be helpful as well?

Thanks, Raj. I'll ask Luisa to answer both of those. First, appreciate your comments about alignment, which was great for us to see. But then how did we calculate the projections of the patient flow on Study 14. Lusia can give you some more details about that and then in terms of the 2158 question about other populations, which is on our agenda as well.

So as I mentioned, the data on the slide is -- the projections on this slide are accurate as we project them currently through the data cutoff last week. And I mentioned that about 1/3 of them have reached treatment week 76. So it's really a mix of confirmed and potential treatment decisions. So we've had 1/3 that have met -- that have already reached week 76 are confirmed. The others, which are projected to come off therapy, have 3 to 6 assessments out of the 7 meeting criteria. So they're on track and projected to come off of therapy.

That's good. And 2158, we started the Phase II proof-of-concept study in E antigen-positive naives to compare to 731, but what about other populations?

Yes. Our initial assessment, as John has mentioned, will be to compare that Phase II proof-of-concept to the 202 population. I think that's really important to get that longer-dosing efficacy data to do a head-to-head comparison of our first- and second-generation core inhibitors. Beyond that, we certainly will look at other populations, including treatment-naive E antigen-negative patients.

So just remember that Rich and his team developed 2158, Raj, to be more potent and it is more potent in cell-based systems at preventing the generation or formation of new cccDNA. So that's not something we're going to see in the 14-day antiviral study. What we saw in the 14 antiviral study is what we expected to see. We saw safety. It's about the same as 731. But to look at this effect against the potency of preventing the generation of new cccDNA, that's why we have to do a longer-duration study. So we can look at the tails of all these antigens and compare it back to 731. So that's the plan, an important point. It's a distinction. But we'd like to look at other populations. Let's start with best where -- we're sort of -- we're still on track to get this trial up and running this quarter despite all the coronavirus issues. So we didn't want to overcomplicate anything else at the current time.

Great. And maybe just one more, if I can. Obviously, I didn't want to comment on the S antigen kind of story, but do you -- from your discussions with the FDA, does this seem as though kind of moving forward, this kind of composite endpoint is how they'll be looking at core inhibitors from here on out?

I can't comment on that, Raj, what they're thinking about that. And I think -- did you mean composite endpoints, where you're meaning DNA and RNA and so forth? Or I'm not sure exactly what you are referring to.

Yes. Yes, the endpoints.

Yes. So look, I'm always reticent to talk about somebody else's opinion, particularly our regulators and let us have all the discussions with them before -- and have those things finalized before we would talk about them publicly. I think that's fair to them and fair to us as well. But it's a good question.

There are no further questions at this time. I will now turn the call back to Assembly's CEO and President, Dr. John McHutchison for closing remarks.

Thank you, again, for joining the call today, everybody. In closing, I'd like to thank our dedicated employees, not only those in the hepatitis B programs, but across the organization. The focus today was hepatitis B, of course, but also our microbiome team, which continues to do great work and is equally committed to our mission. I'd also like to recognize the investigators involved in our trials, the patients participating in the studies and the shareholders who support our work. You are all essential to the progress we are making toward our vision of a cure for hepatitis B. I'm confident we have the resilience and the resources to push forward our goals for this year and afterwards and beyond that as well. So we look forward to updating you in the future, sharing our continued progress. And thank you today for your time, and this concludes our call.