Please be advised that today's conference is being recorded. I would now like to hand your conference over to your speaker today, Lorna Glaser, Senior Vice President, Investor Relations.
Thank you, and please go ahead, ma'am.
Good morning, and thank you for joining us as we've discussed today our company's 2 presentations at the liver meeting, the 2019 Annual Meeting of the American Association For the Study of Liver Diseases currently being held in Boston. We are pleased to share the encouraging new data for 731 and Q158, our 2 lead HBV core inhibitor candidates featured today in 2 late breaking poster presentations. In a moment, I will turn the call over to Doctor. John McCutcheson, Assembly's CEO and President, to set the stage with some introductory remarks and then Doctor. Richard Colono, EVP and Chief Scientific Officer of Virology, will review the data that are being presented.
Following the prepared remarks, we will open the call for Q and A. The slides we will refer to during the call as well as the posters and press release issued this morning may be accessed in the Events and Presentations section on the Investors page of the assemblybio.com website. As a reminder, today's conference call will include forward looking statements, including statements regarding our research and development program, evaluation of interim data, the timing of clinical trials and therapeutic potential of our development programs, including 731 and Q158. These statements are subject to the Safe Harbor protections provided under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from these forward looking statements due to numerous factors, including those discussed in the Risk Factors section of our Form 10 Q for the quarter ended September 30, 2019, which was recently filed with the SEC.
John, I'll now hand the call over to you.
Thanks, Lauren, and welcome to everyone on the call today. I'm particularly pleased to be in Boston at AASLD again that our presentations provide us the opportunity to talk with you all about assembly's vision and our broad portfolio of core inhibitors, which hold great promise as a central part of future potential curative therapeutic regimens for patients with chronic hepatitis B infection. This transformative potential for the many millions of patients globally with chronic hepatitis B and the quality of science and the teams driving it are precisely what attracted me to join assembly. As you will learn from our presentation today, we are seeing exactly what we would hope to observe at this stage of development, namely favorable tolerability data in combination with nukes with once daily oral dosing. Secondly, antiviral activity for the 731 Nuc combination is superior to standard of care Nuc monotherapy in terms of both DNA and pgRNA reductions using sensitive assays.
And in the absence of ALT elevations, a subsequent decline in viral antigens, which are surrogate markers of the cccDNA pool and its depletion, which will be necessary to cure patients. We have had an exciting few days here at the meeting. Positive feedback from researchers, clinicians, scientists and the broad liver disease community as well as our industry counterparts. I am even more excited about the year ahead as I believe we are strongly positioned heading into 2020. Before Rich takes you through the data carefully today, I'd like to briefly set the stage with regard to our hepatitis B programs, including what we have achieved to date, where we are heading and what to watch for in the future, and what we are learning about hepatitis B in the field in general.
First on Slide 4, I would like to outline our vision to bring the quarter of a billion people chronically infected with hepatitis B worldwide closer to a cure. As with hepatitis C, we believe the combination regimens with complementary non overlapping mechanisms will be required to completely suppress hepatitis B viral replication and different treatment regimens may be needed depending on the patient population and their treatment history. To date, both 731 and 2,158 have shown favorable tolerability with once daily dosing, as I said, and we believe that the emerging data for 731 support dosing when combined with the standard of care Nuke therapy. Our initial approach to cure includes the combination of a core inhibitor and a Nuke. Ultimately, a simple all oral regimen that is well tolerated will be the ultimate winner for the many millions of infected patients worldwide.
Slide 5 now outlines our development strategy. Today, we are focused on the first and second waves with our 1st generation core inhibitor candidate 731 that has shown faster and deeper declines in HBV DNA and PG RNA when added to the Nuc therapy than with Nuclease. The 211 extension study of 731 plus nuke therapy continues currently. And over the course of 2020, treatment will be consolidated and eventually withdrawn to see if viral suppression can be sustained in some patients. In parallel, we are continuing regulatory discussions and shaping our clinical trial plan to advance our portfolio into later stage and registrational trials.
We are also getting an early look today at initial data from the 1st cohort of patients in the Phase Ib trial of 2,158, our next generation core inhibitor candidate, shown as our second wave in the middle of the slide of more potent core inhibitors. During Q1 2020, we expect to complete that study and to begin a Phase 1 healthy volunteer study for our 3rd generation compound 3,733. We are also in parallel looking at the potential to pair the core inhibitor new combination with other complementary mechanisms through carefully executed scientific cross company collaborations. In this fashion, we believe our core inhibitor programs could be central to multiple regimens and programs aimed at finite curative potential strategies. In terms of our clinical objectives, we have always believed that the cure for chronic hepatitis B infection would need to be pursued in a stepwise fashion.
Slide 6 gives a sense of assembly's approach. The data we have generated from our Phase II studies to date with 731 suggest we have achieved the first three of the objectives shown on the slide. We will be observing the Study 211 subjects for further viral antigen declines with continued consolidation of therapy, during which we hope to see sustained DNA and RNA suppression. And then finally, treatment withdrawal with both of those events anticipated during 2020. As we work on finalizing our criteria for withdrawal of treatment for the patients currently enrolled in Study 211, we continue to evaluate which biomarkers may be best to predict potential cure.
Assembly is focusing on sensitive assays using HBV DNA as well as pre genomic RNA since these are the primary surrogate markers for cccDNA transcription. Rich will also outline that we are now observing associations with pgRNA declines and subsequent declines in other transcripts of cccDNA like E and core antigen. We believe this is novel, only observed with core mechanism to date and therefore reflects the decreasing pool of cccDNA, a prerequisite for eventual curative regimen. With that broad and high level introduction to our approach and vision for what we hope to achieve for patients with hepatitis B, I'll now turn the call over to Rich to review the AASLD presentations in detail.
Thanks, John, and good morning, everyone. I certainly share John's enthusiasm for the data we are presenting today. I'll start on Slide 7, which provides an overview of patient metrics for our Phase II studies on 731. Today, we are reporting final week 24 data for the NUC suppressed and treatment naive patients in studies 201 and 202, respectively, as well as interim data for study 211, the ongoing long term extension study where all patients receive combination therapy. Of the 97 patients completing Study 201 and 202, 87 have currently received combination therapy in Study 211 for a minimum of 16 weeks with cumulative treatment times of greater than 40 weeks for those who have received the combination from day 1 in studies 201 and 22.
To increase our ability to detect very low levels of viral DNA and pgRNA, we developed and utilized highly sensitive assay meta assembly to supplement the commercially available colos DNA assay. These new assays enabled us to quantitate viral DNA down to 5 international units per ml and pgRNA down to 35 units per ml. Slide 8 lists the demographics and baseline characteristics of the patients enrolled in the original 201 and 202 studies. Patients were predominantly Asian and infection was mostly with viral genotypes B and C. Of particular note was the relatively normal range of ALT levels and the presence of high levels of PGRNA in all patient populations.
Now turning to the results on Slide 9. In the left graph, treatment naive patients in Study 202 who received 731 plus standard of care and tecovir therapy resulted in a faster and more significant decline in DNA levels in the 1st 24 weeks of treatment than entecavir alone. In addition, on the right graph, the combination of 731 plus entecavir exhibited a rapid 2 log decline in PG RNA levels, something not observed with standard of care Nuke therapy. We believe this initial rapid phase decline of PG RNA is mechanism based inhibition, meaning that packaging of the PG RNA is blocked and PGRNA is simply trapped in the infected cell, unable to be secreted and subsequently detected in the plasma. Importantly, we believe the 2nd slower phase decline in pgRNA over time reflects the decay and actual reduction in cccDNA levels.
More on this later. Let's now turn to treatment of nuke suppressed patients in Study 201 on Slide 10. The objective of
this study was to see
if the addition of 731 to ongoing nuke therapy could drive the persistent residual viral levels in these patients to undetectable levels or to target not detected. Most of these long term patients harbor low level viremia at study entry. Using a highly sensitive PCR gel assay, we were able to confirm that a high percentage of the e antigen positive patients examined did indeed have detectable viral DNA at the time of study entry despite years of prior Nuke therapy. The addition of 731 to their ongoing Nuke therapy caused 81% of those treated with the combination to achieve target not detected by week 24 versus 0 of 12 Nuc patients who received Nuc alone. We view this as an important result as we believe the inability of Nuc therapy to eliminate this residual level of infectious virus likely accounts for the inability to cure patients with those therapies.
These patients also harbor significant levels of PG RNA as new therapy has little effect on reducing cccDNA levels despite years of treatment. As with treatment naive patients, the addition of 731 caused a rapid reduction in pgRNA levels, while patients continuing on Nuc therapy alone showed no change in their PG RNA levels over 24 weeks. The last two slides represent the final viral nucleic acid results for the initial 6 month studies, 201 and 202, showing faster and deeper declines in HBV DNA compared to new therapy alone, down to target not detected levels and significant reductions in the levels of pgRNA, the primary surrogate marker of cccDNA, to the lower levels of quantitation. Now let's turn and take a look at the interim results for extension Study 2 11. Slide 11 shows that the original 202 treatment naive patients on entecravir who switched to combination therapy saw immediate and enhanced declines in both their HBV DNA and PG RNA levels.
And those treated throughout with 731 plus Entecogir combination achieved mean DNA and PG RNA declines of 6 in the 2nd phase decline of pgRNA levels, which we believe reflects reductions of cccDNA pools. When we look at nuc suppressed patients in 2 0 1, who are now in Study 211, this is on Slide 12, the switch from nucolone to the combination showed an increase in the number of patients achieving both DNA target not detected and in reductions of PGRA levels to less than 35 units per ml. Both of these thresholds were only achieved when 731 is part of the treatment regimen. As I mentioned earlier, we believe that the secondary decline phase of pcRNA reflects the decay of cccDNA pools. If true, then the magnitude of that decline should correlate with the decline of other surrogate markers of CCC units, namely B antigen and core antigen.
And to a lesser degree, S antigen as the latter can also be produced from integrins, which a core inhibitor cannot inhibit. As a reminder, while integrated HBV DNA can produce S antigen, it cannot produce pgRNA or infectious virus. Stratifying the pgRNA declines achieved by the original 21 patients from Study 202, who are now in Study 211 into 3 categories, greater than 3 logs, 2 to 3 logs and less than 2 logs in the table at the top of Slide 13 showed PT RNA reductions of 3 logs or more was highly correlated with higher mean declines in viral antigen. Specifically, 11 or 52 percent of these 21 patients who exhibited greater than 3 log declines in Ptrna had mean declines of 1 log of e antigen, 1.4 logs of core antigen and nearly a log of S antigen. This was not driven by just a couple of patients as 82% 91% of these 11 patients exhibited E and core antigen declines of greater than half a log, respectively, while 55% showed greater than a half log decline in S antigen.
Lower mean declines in percentages of patients showing a half a log antigen declines were observed in those patients failing to achieve a 3 log decline in pgRNA levels. It is important to emphasize that 20 of the 21 patients in this overall group had normal ALT levels less than 40 units per liter, indicating that these declines were due to the activity of 731 plus emtekavir and not immunologic flares. The graphs at the bottom of the slide show the individual antigen declines for the 21 patients summarized in the table above. The x axis shows the log decline in PTRD and the y axis shows the log decline in either E, core or S antigen. The results shown in the left and middle graph show a clear correlation with PgRNA declines, while the plot of S antigen on the right shows a similar correlation but lower overall declines in S antigen due to the fact that S antigen is partially derived from integrin and not CCC using.
The correlations illustrated in these graphs have our values that are statistically significant. These data offer the strongest evidence to date that direct acting antivirals can reduce cccDNA levels in the absence of ALT flares, a result we are truly excited about and we think a breakthrough in field. Now moving on to Slide 14. For nuke suppressed patients originating from Study 201, surrogate markers of cccDNA started at much lower concentrations, so the dynamic range of declines for analysis is much more limited. Nonetheless, among the 27 B antigen positive patients receiving 731 plus NUC for greater than 40 weeks, 18% or 67% were both HBV DNA target not detected and had PGRNA levels less than 35 units per mL, with 10 of these 18 patients also having e antigen levels less than 1 international unit per mL.
Interestingly, while drops of greater than a half log in both e antigen and or core antigen were observed in several patients, only one patient had that magnitude of decline in S antigen. This is consistent with recent studies indicating that a high percentage of S antigen in these long term infected patients can come from integrands and not cccDNA. Again, these changes occurred without flares as ALT levels in 25 of these 27 patients was again below 4 units per liter. Turning now to safety and tolerability data. We are pleased that the 731 new combination has been has shown favorable tolerability data with prolonged therapy.
Overall, 731 has been administered to 276 subjects in several clinical studies, with 126 patients treated for at least 4 weeks and 87 patients treated for 12 to 60 weeks. These data further differentiate 731 from other core inhibitors that have faced challenges and limitations in dosing to optimal therapeutic levels. Slide 15 shows final tolerability data over 24 weeks in studies 201 and 202, with similar findings observed thus far in Study 2 11. 731 was well tolerated when administered with ANUCE for 24 weeks. 26 of the 58 subjects reported no adverse events.
And of the 32 reporting 1 or more AEs, all were grade 1 or 2. No serious AEs were reported. 5 of the 58 patients receiving the combination reported a rash. 4 were Grade 1 and 1 was Grade 2, no systemic signs of laboratory abnormalities were observed and all patients continued therapy through week 24. Slide 16 outlines the laboratory findings for studies 201 and 202.
Overall, the abnormalities observed were grade 1 or 2 in severity occurred in similar portions of patients across the 2 treatment groups. With longer term treatment in 211, the nature, frequency and severity of laboratory abnormalities have been similar thus far to those observed at week 24. Grade 3 elevations in ALT and or AST have been observed in only 3 patients treated in the combination beyond week 24. However, it is important to note that in 2 patients, the elevations were transient and normalized within 4 to 8 weeks, while continuing on treatment. In the 3rd patient, ALT and AST levels fluctuated during treatment between grade 3 and grade 2.
And that at week 52 of the combination therapy, there were no signs of hepatic decompensation, increase in direct bilirubin or decrease in albumin. Most importantly, all three of these patients remain on treatment. In summary, on Slide 17, we are really encouraged by the potent antiviral response, the emerging signs of the cccDNA pool diminishing and the tolerability data we have seen and are continuing to see for the 731 plus nuc combination in patients treated for 40 weeks or more. The combination demonstrated faster and greater reductions in DNA and most importantly, PgRNA than new therapy alone. With DNA target not detected and pgRNA below 35 units per mL thresholds only achieved in patients receiving the 731 containing combination.
2nd phase declines in pgRNA, the primary surrogate marker of cccDNA of greater than 3 logs were strongly associated with reductions in viral antigens, suggesting declining cccDNA pools and 731 has been very well tolerated in combination with new therapy with no serious adverse events reported to date. In the last few minutes, let me turn briefly to our other poster presentation at ASLD, highlighting early data for our 2nd core inhibitor 2,158 shown on Slides 18 19. In vitro-two thousand one hundred and fifty eight exhibits 10 fold enhanced activity in blocking the virus and also blocking cccDNA formation. In our ongoing Phase Ib monotherapy studies in HBV patients, potent antiviral activity has already been observed now in the initial low dose cohort of 100 milligrams in e antigen positive patients treated for just 14 days. HBV DNA and pgRNA declined at 2.3 logs and 2.1 logs, respectively, have been observed.
We believe that the PK profile observed also supports once daily dosing. 2,158 has been well tolerated with no AEs or lab abnormalities beyond grade 1, except for one patient with grade 3 cholesterol and grade 2 triglycerol levels that were already grade 2 and grade 1 respectively at baseline. A grade 1 rash was reported in 1 patient with no accompanying systematic signs or lab abnormalities. It was transient and resolved within 24 hours without treatment. The trial is ongoing with the 2nd dose cohort enrolling at 300 milligrams and we anticipate the study to be completed during the Q1 of 2020.
I spent much of my career working on antivirals for hepatitis B, hepatitis C and HIV, but curing chronic hepatitis B patients has proven to be the most challenging. But the field is learning more about what to look for on the path to cure and these latest data give us confidence that we're making solid progress on that path. We are looking forward to seeing further data from the 211 study in 2020, particularly as patients come off therapy and to advancing our core inhibitors toward registrational studies and eventual regulatory submissions. With that, John and I are now happy to take your questions. Operator, would you please open the Q and A session?
Thank you. And our first question comes from the line of Geoffrey Porges with SVB Leerink. Your line is now open.
Thank you very much for taking the questions and for the overview presentation. Rich and John, just a couple of questions on your slides. First, could you on Page 11, the second chart of PG RNA levels, it shows a drop off between week 50 week 60. Could you confirm that that's just very small patient numbers? And Or could you give us a sense of how many patients that are in the 211 cohort out at that 50 to 60 week duration?
And then secondly, in the regression analyses, particularly on the surface antigen, it looks as though that chart that graph is very much driven by the 4 outliers. Could you talk about the outliers? And then lastly,
I don't really know what
to make about of surface antigen because you're saying here that the if you look focus on the sort of 10 patients that have the higher reduction in PG RNA then you're getting a significant reduction in surface antigen. So should we be expecting you to engineer your development strategy and your combinations towards reductions in surface antigen? Or should we be sort of ignoring surface antigen? And then sorry for the long list of questions. Lastly, could you perhaps comment on competitor data, which I'm sure you've seen, suggesting that the addition of a core inhibitor to the combination of an oligo and a nuc didn't add anything in terms of benefit.
Okay. Thanks for the long list of questions. So if I can just start with the first one, the easiest one. Yes, the last time points on those graphs, Slide 7, cholabegis are 1 or 2 patients, 1, 2 or 3 depending how far back he goes, especially the last time points. So I would just ignore that.
It's really just the decline from 2 logs to over 3 logs that we're really concentrating on and that's the correlation with the data that we have.
Great.
Okay. The second question about correlation data. Okay. Again, it's just these are the 21 patients and each dot represents the actual antigen level for each of those patients. And it's just really to point out the correlation.
Yes, you only get these large declines in those patients that have significant PGR decline. That's the only statement we're trying to make here, which no one has ever shown before. And we've always predicted that PGR today is the primary marker of cccDNA because there's no other source of pgRNA. It only comes from cccDNA. So the fact that when you do demonstrate that you can drop ttRNA levels significantly, we found that significantly beyond the 3 logs, you start seeing these more dramatic effects.
So we would anticipate that as patients continue to be treated and we drive the RNA levels down in more patients, we're going to see these levels of antigens continue to go up. But as you can see, the P values there are very strong, 1. So clearly, these are highly significant data even though it's a small data set. But the obvious correlation even with the table in terms of how you see the means and the number of patients that actually even have any kind of significant decrease go down as the pgRNA does not go down, also gives us a lot of encouragement that we are on the right track with this as the primary marker of CCC.
Jeff, it's John. You'll ask two questions of the 4 you asked. So S comes from 2 sources. It comes from cccDNA and it comes from integrated virus, as you know. So that explains the difference in the correlations.
Our focus will be on antigens that aren't integrated. So if we see depletion of the ccDNA pool, we'll see pgRNA go down. We'll see E and core go down. And that will be the focus of the way we attempt to predict what will happen and how we will stop therapy in the future. Regarding the competitive data, we were not surprised at all that a short 4 week duration of study would show any difference.
So we didn't see all of the PGRNA data, of course. But given what we have found and understanding the half life of cccDNA, the need to prevent replenishment, you wouldn't expect to see these things change in such a short period of time. So we were not surprised by that. So thanks for your questions, Jeff.
Great. Thanks for the answers.
Thank you. And our next question comes from the line of Raju Prasad with William Blair. Your line is now open.
Great. Thanks for taking the question and congrats on the data. One question on maybe kinetics of the decline in antigens as it relates to pgRNA. Could you just comment on when you started seeing kind of that depth of response in the patients with
the 3 log increases or the
3 log decreases of PGRNA? Was it 12 weeks afterwards or was it kind of concurrently with the pgRNA?
Yes. No, that's a great question. And if you actually go to the poster, we didn't go over that data here. And look at individual patients, you can get a sense of that. We have what I call the resuscitation that literally was on Entekavir for 6 months, pretty much flat lined everything for 6 months.
And then as soon as that patient went on to 211 in the combination therapy, all the antigen just went over a waterfall. It went down very dramatically. So that indicates that, that effect, if the drug is truly effective in that person, okay, whether absorption or just sensitivity that patient has, you can see these dramatic effects in as short as 12 weeks on combination, whereas others would take much longer. So it's going to be an individual patient kind of basis thing as we develop this data. But we have a whole range.
The relationship is not time based, saying that only the patients that are out 40 plus weeks or 50 weeks have these effects. It can actually happen sooner. There's a range of activities, but it's patient specific.
Great. And 2 more, if
I may. Does this PG RNA kind of leading indicator, does that change your thoughts on what you're going to do with 2,158 just given the increased potency there? It'd just be kind of interesting to hear your thoughts on kind of clinical development moving forward with these next gen candidates, although your lead program is obviously far ahead.
This is Rich. Yes, clearly, our thinking hasn't changed. If you remember way back, if you follow our presentation, we've always believed pdRNA would be the primary predictor of cccDNA. And we also have based on also what John said and what I said earlier, the turnover of cccDNA is 3 to 4 months, okay? So there's no immediate effect you're going to get, but even if you start to inhibit PG RNA today, it takes a while to decay away what's there.
But it's not going to actually change how we develop 2,158. We just it's clearly our primary marker and we want to be able to drive that RNA down to really undetectable levels. And if we can get it down to the lowest levels possible, which is why we developed these more sensitive assays and that will be a key driver going forward in terms of when the next phase of when we actually take patients off, we put them into the consolidation period before taking them off. So the PG RNA is a primary driver for us.
Rajul, it's John here just to add on. So and it's important for everybody listening to understand that these 2nd and third generation compounds have been designed to be more potent in terms of their ability to prevent the generation of cccDNA in a cell based assay. So you won't see that in the 14, 28 day viral decline curves, which is what we're showing partly in the first cohort in our post. But next year, we've got to dose for longer, got to look at the slopes of the RNA declines to make sure we're there. And then we need to look at antigen declines.
If our drugs are more potent, those antigen declines should occur earlier if we're shutting off the TAPTIS cccDNA and replenish it more effectively. So please be aware of all those things that we need to look for next year.
Great. Thanks again. Thank you. And our next question comes from the line of Salim Syed with Mizuho Securities. Your line is now open.
Hey guys, congrats on the data and also for fitting so much data onto one poster. So kudos to whoever committed the poster. 3 from me, if I may. 1 on when you're thinking about the relationship between baseline S antigen levels and then how many of those patients actually went to E negative or became under 100 units. Could you maybe describe that relationship, what we know about that relationship so far?
2, on genotyping, it looks like in the poster, genotype C patients have slightly flatter slope in pgRNA. Is that something that you can draw a conclusion from? Or are we still looking at genotype C? And then lastly, just on safety, it looks like the 3 patients had ALT AST elevations. Is that due to the it looks like they're uncommon.
Is that due to the core inhibitor or the nuke that we know? And also what does that say about safeties for the corn inhibitors given you guys have used novel chemistry?
Okay. Celine, why don't I start with the safety first, and then I'll let Rich take the other 2. We're careful describing the 3 Grade 3 ALT elevations as Rich described to you today. We thought they should be included. They're in the open label extension study of the trial.
So just recall from the graph we showed you, in the 1st 24 weeks, the rates of grade 1 and grade 2 elevations of AL2 were actually in the new car and there were no grade 3 elevations. All unless it's rare and idiosyncratic occur within the 1st 8 to 12 weeks. These observations beyond 24 weeks are isolated. 1 was ALT only, the other was AST only, the other was fluctuation. So I believe they represent the natural history of fluctuating disease as we continue to observe patients continually.
The patients all continue on treatment. There's no bilirubin elevation or evidence of any hepatic impairment. So this is highly under drug induced liver injury occurring late in the development of the program. Rich, I'll let you ask answer the other question about baseline surface and genotypes.
In terms of genotype, no backwards, I'll reverse order. Again, genotypes, these compounds are they will work against all genotypes. We've never found any differentiation between any particular genotype in terms of its ability to inhibit. So I think you're just looking at a very limited data set. And so I wouldn't isolate one patient and have that be represent or feel that that's representative of some genotype of HBV.
In terms of S antigen baseline levels correlating with anything, no, there is no correlation whatsoever with baseline. I mean, pretty much all the patients have a fairly tight range unlike the other antigens, a pretty tight range of between 1,000 plus upwards to almost 50,000 to 100,000. So there's that couple of wild wins. So there's no real relationship with which patients drop the most, etcetera, based on their baseline.
Small numbers of patients here. So making inferences about different genotypes and different responses and everything is really premature. I think we need large data sets and more information as is usually the case with early development.
Yes. It's really about that group of 21 patients, which is pretty dramatic, okay, when half of them have such a dramatic response and the correlations are so strong. And again, it's really the greatest example we have of this correlation between pgRNA really being reflective of cccDNA pools and being having the confirmation that the antigens go down in parallel with the pgRNA. We always said that there are 3 or 4 surrogate markers of cccDNA and that they should all go down in some kind of parallel fashion. If you had one go down and not the others, it would make little sense.
The only exception to that and the complexity is
that we're seeing in the
patient. Versus another patient, we can get 3.5 log drops in SA antigen because that patient probably has most of their esteroids from CCC DNA. So I think as we continue to treat patients, we're going to see this variety of responses on S. And that's why we feel S is less predictable of what we're really trying to achieve and that is to try to exhaust the CCC in April.
It's John again. I think it's complicated the data sets for everybody. But I think the important thing is half of them have a 3 log or greater decline in PG RNA. These declines in PG RNA, we've shown you in the randomized 24 week first parts of the study, don't occur with the NUC. So this is an observation that you would expect to see in any other sense.
And then the only source of pgRNA is cccDNA. So it's actually a very beautiful scientific story that's developing here so far. So we're excited about that. And we're going to play it out next year. We're going to consolidate.
We're going to take people off therapy after a period of consolidation and see what happens, see if we can prevent relapse of HBV DNA.
Okay, excellent. Thanks so much guys and congrats again on the data.
Thank you.
Thank you. And our next question comes from the line of Michael Yee with Jefferies. Your line is now open.
Hey guys, thanks. Congrats, Sean and Rich, on the updated data. Two questions. On Study 201, Can you just maybe characterize how you're thinking about the use of this data as the development for the next stage? I know you talked about consolidation and all that for next year.
What in your opinion would be the perhaps response criteria to take people off? That patients under PGR are less than 35 units. Maybe just talk about how you're thinking about what the response criteria would be or it'd be a time based criteria? That's question 1. Question 2 is for Study 202, same situation.
How are you thinking about what you see between the difference in combination versus monotherapy? And then what happens when you switch people on to combo? Again, is that some sort of time based therapy? I know there was discussions with FDA about developing something there and using DNA, etcetera, as an endpoint. So maybe just talk to what that result means for the next steps in that type of population?
Thanks.
Okay, sure. This is Rich. I think the again, the objective is to get into the next stage, the 4th stage, if you will, of this consolidation. So one of the markers have to get to before we decide we're going to put them into consolidation mode. Again, consolidation mode being we really can't see anything else happening.
We continue to treat to make sure we get down to even lower, get rid of those less kind of molecules. But the criteria for both patients or all patients for the most part is pretty much the same. We expect DNA to be target not detected. We have to show or at least have convinced ourselves that the patient has reached a point where there's no more active virus that we could detect. So target to have the RNA and we're trying and we're actually working on another assay to almost a target not detected in terms of RNA.
If you can truly show that you have no detectable DNA, so no viral replication, no detectable RNA, pgRNA, so therefore no evidence that cccDNA is still there, I think that would be the baseline sort of trigger for a consolidation period. But we are having internal discussions on exactly whether we should add something else to that, what we call double negative, whether we throw in as an e antigen level or whether there's some other antigen related level, those are still for us. But those ground rules will apply to all patients. And a patient population androgen negatives in 201 are actually most advanced in that entire process. And we don't talk about it because there's really nothing to talk about with those patients.
They are E negative. Their core antigen is basically barely detectable. Their RNA and DNA in most of those patients are already at this very, very low level of even our assays. So for the most part, one can think mentally, those are actually already in a consolidation mode. And those probably will be the first ones that we would take off and see if there's a virologic rebound.
But working backwards, so we have the antigen negative, highly suppressed. We have the 201 patients, which were are probably the most exciting for us because of the dynamic range of all the markers. It's the original patients that were naive that we've already brought down now to where patients in 201 started. So all of these patients, and that's the beauty of our 2.0 Phase II design, we have a variety of patients. They're all at different stages.
They're antigen positive, negative, suppressed, unsuppressed. And so they're that just gives us a wealth of data in terms of following the progression of all these patients, but they all get to the same point at the end of the day.
Hey, Mike, it's John. Can you hear our response? I've heard that the line is cutting in and out. Can you hear what Rich said?
We hear about 80% of it. It does kind of break up a little bit, but we hear about 80% of it. And then for my follow-up question for both and then that's okay. My follow-up question is that based on all of the data you just said and all the criteria, does the 2nd generation drug for you just philosophically get more patients or a higher percent of patients to this criteria in the same amount of time and or just faster? That's the point of that molecule.
That would be the hypothesis that we can do this more efficiently in more patients more rapidly by shutting down cccDNA generation more effectively. Correct, Rich?
Yes, correct.
Yes, that's right, Mike. So look, stay tuned. When we have the stopping criteria approved and agreed upon, we can talk about them. But nobody stopped yet, and we're in the process of actively working and thinking about this Right now, it's fairly advanced.
Perfect. Thanks so much.
Thank you. And our last question comes from the line of Brian Skorney with Baird. Your line is now open.
Hey, thanks guys. Port just asked most of my questions, but maybe helpful for
a couple
final ones in there. Just in terms of the when I look at the individual patients in the poster and you kind of brought up that one who saw a decline from everything other than S antigen. I mean, how do you think about if you're shutting down all the viral markers and you are seeing hepatocellular turnover, why wouldn't S antigen at least start declining in that patient? And just out of curiosity, is there any marker you could use for hepatocellular turnover that's non virally related just to kind of try to observe and measure what the time frame would be to ultimate turnover of hepatocytes here? And if it varies patients?
Yes. Well, Astana give me comfort for that turnover because like I think we believe in that one patient because it's a complete disconnect with the other markers. If AstanaGen is just not going down very rapidly or if at all, I think one can imagine that in that particular patient, there's a high percentage of integrins providing that S antigen. And so as we continue to treat, you can remember, we haven't as John said, we haven't taken patients off therapy yet. So if therapy goes another year overall, by the time we get down to the levels we want to get to and then consolidate for at least 6 months, then by that time, we would expect that actually turnover of hepatocyte is also taking place.
If we truly have prevented new viral replication, new CCCs and a synthesis, we should also prevent new integrins, okay? And so the existing integrins should die off over time. So that's why I think in that particular patient, for instance, and there are patients like that, that no effect on S, that presence of S is actually our surrogate marker for cell turnover because the only way core inhibitors can turn that over is by the cell dying, okay? So we stop new cells having integrins and the cells that have the integrins have to die out. So we just have to follow that over time.
We can't answer your question directly. We don't have any marker that we follow specifically. But one would anticipate that etsanogen will eventually decline, but through a different mechanism. And that mechanism could catch up in terms of time, but we just have to see. But one could envision, okay, at the end of the day that you could literally get to a person who has no more viral replication going on, cccDNA levels, if it's possible, have disappeared and they could still be expressing S.
But that patient is not going to be infected by the S, okay, or influence at all. It's going to be a scar that you were infected with hepatitis B. I mean S is not the driver of chronic infection. It is a simplified, it is a sign and a diagnostic tool, but it certainly isn't the driver of infection, the virus is. So our target store remains on the virus, on the CCC G and A, and we'll just have to follow and see what happens with that same.
Ryan, it's John. Just to add to what Rich said, the half life of an infected hepatocyte is unknown. I've actually been asking a lot of people for their answer to that question and I get dumbfounded look, but it stays to weeks. And so you would expect that if you shut down to answer your question, it's Richard, if you shut down completely shut down viral replication, over time, surface antigen should decline through loss of infected hepatocytes. And how long that takes, nobody knows.
It depends on the half life. So there we are. Just recall, Brian, that you don't need to show clearance of surface antigen to reach the regulatory endpoint of a finite therapeutic cure. Absence of DNA 6 months after cessation of therapy, SVR-twenty four for HBV DNA is an approvable endpoint without change in surface antigen for a hepatitis B therapeutic regimen. That's an important point of distinction.
Thank you. And that concludes today's question and answer session. I would now like to turn the call back to John McCuttenson, CEO and President, for any closing remarks.
So thanks. Thank you to you all for your time and attention today. We're very encouraged by these latest data for our lead core inhibitors. This is particularly exciting for me because I chose to join Assembly to tackle the challenges of hepatitis B and to move the field forward. I think we're doing that now and we're showing you some evidence of that.
We are now seeing that evidence that we are heading in the right direction and the combination of 731 plus and nuke has been well tolerated and has shown the ability to eliminate residual viral replication, some patients achieving DNA targets not detected with sensitive assays, more than 3 log or multi log reductions in pre genomic RNA and antigen decline suggestive of a diminishing cccDNA pool. These are significant first steps and obviously there's much more we need to do. The extended treatment duration Study 211 and 731 plus the mute continues. And during 2020, as we've said today, we will consider patients for consolidation and then they'll eventually come off therapy so we can assess whether viral suppression is sustained. We expect to provide additional updates from this study next year.
During the Q1, we also anticipate completion of the Phase Ib trial of 2,158 and the start of a Phase 1 for 37 33, our 3rd core inhibitor candidate. We believe assembly is in a strong position as we head into 2020. We're excited about the prospect of advancing our core inhibitor portfolio into later stage trials. So thank you for joining today's call. We look forward to communicating our progress in the New Year.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.