F-Star Therapeutics Inc (FSTX) 2018 Q2 法說會逐字稿

Good day, and welcome to the Spring Bank Pharmaceuticals Second Quarter 2018 Corporate Update Conference Call. At this time, I would like to turn the conference over to Marty Driscoll, CEO of Lifestyle Advisers. Please go ahead, sir.

Good morning, everyone, and welcome to the Spring Bank Corporate Update Call. Just as a correction, I'm actually the CEO of Spring Bank Pharmaceuticals. This is Marty Driscoll, and I'm happy to be chatting with everyone this morning. Joining me this morning on the call is Dr. Ned Afdhal, the Chief Medical Officer at Spring Bank.

I think many of you that know us know that, typically, John Freve, our Chief Financial Officer, joins us on these calls. John has experienced a death in his family and won't be joining us this morning.

Before we begin our discussion of the update, let me show you our forward-looking statement. Before we begin this presentation, allow me the opportunity to mention that in today's call, we will be making forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from those projected in the forward-looking statements. Additional information regarding these factors is discussed under the forward-looking statements section in the press release we issued this morning as well as in Spring Bank's SEC filings. Forward-looking statements during this call speak only as of the original date of this call, and we undertake no obligation to update or revise any of these statements.

Ladies and gentlemen, this morning on this call, we're excited to present to you a summary of the compelling data that we have generated for our oral immunomodulator, inarigivir. This is from Part A of the ongoing Phase II trial in chronic HBV patients. Specifically, Dr. Afdhal, in a few minutes, will detail the positive results from cohort 3 of the inarigivir dose escalation ACHIEVE trial. I hope all of you saw the press release that we issued this morning just about an hour to 1.5 hours ago.

As you are likely aware, cohort 3 of our ACHIEVE trial involved the administration of inarigivir 100 milligrams once daily for 12 weeks followed by tenofovir disoproxil fumarate, or as we all know it, Viread, once daily for another 12 weeks. We are excited by the results from inarigivir from this 100-milligram cohort because the data continue to demonstrate an excellent dose response on the key anabolic parameters for chronic HBV.

It's this cohort 3 data reveals that inarigivir continues to demonstrate impressive dose-dependent responses on both HBV DNA and HBV RNA. The data also continues to reveal to us that inarigivir is the only oral treatment in the HBV development space that has demonstrated a clinically meaningful effect on hepatitis B surface antigen. With the 3 ACHIEVE cohorts combined, the inarigivir treatment arms have demonstrated a predefined surface antigen response in 28% of patients with a mean reduction of almost 1 log.

As you read the press release and as we've announced this morning, we are also pleased to report to you that our partners at Gilead are significantly expanding the clinical work they are conducting with inarigivir in HBV. Gilead is adding 2 cohorts to their ongoing inarigivir 50-milligram plus Vemlidy clinical trial to include new cohorts involving the administration of 200 milligrams of inarigivir plus Vemlidy in naïve HBV patients and 100 milligrams of inarigivir in Nuc-suppressed HBV patients.

In addition to the extensive additional data these new cohorts will provide to us, the Gilead expansion will save Spring Bank a substantial sum in previously planned clinical costs due to the fact we will no longer need to conduct Part B of our ACHIEVE trial, which is -- was to be our own Phase II inarigivir plus the Nuc coadministration trial.

Another important benefit of the Gilead clinical trial expansion is we can now accelerate our own Phase IIb/III clinical program for inarigivir and our fixed-dose combination product, SB 9225. We are quickly enrolling the patients in the fourth and final cohort of ACHIEVE Part A, our Phase II trial, involving the 200-milligram inarigivir monotherapy, and we expect to complete the randomization of this cohort in the next few weeks.

Together with the benefits of the Gilead clinical trial, the collaboration expansion and the completion of the fourth and final cohort of the 200-milligram monotherapy, here -- or later in the fourth quarter, we will be in the position to enter the first of multiple Phase IIb/III trials early in 2019. Once you have the opportunity to hear and see Ned's plans, it will be evident to you that Spring Bank will be embarking on a clinical program addressing multiple HBV patient populations and will have the most expensive Phase IIb clinical program in the HBV development space.

So with that, I'd like to now turn over the discussion to Dr. Afdhal, who's going to take you through the cohort 3 data as well as our clinical plans and give more details on the Gilead clinical trial expansion.

Good morning, everyone, and welcome to our HBV clinical update. Just to remind you of the mechanism of action of inarigivir is a selective immunomodulator. The action of inarigivir is mediated through its interaction with RIG-I. It is a RIG-I agonist, and it enters the hepatocyte through OATP1, has a concentration of 25:1 in hepatocyte to plasma, and when it enters the hepatocyte, it binds to RIG-I and it activates the RIG-I responses within the hepatocyte, giving it a selective immunomodulation. This results in the release of Type 3 interferons, and also by binding to RIG-I and activating RIG-I, the RIG-I SB 9200 complex is able to interact with the HBV pregenomic RNA to give a secondary antiviral effect. The primary effect is through the immunomodulatory mechanism of the RIG-I activation.

we have significant data on the mechanism of action, which we have expanded over the last 6 months. We now know the binding site of inarigivir to RIG-I. In particular, this exciting data generated by our collaborators shows that inarigivir binds selectively to the CARDs domain and to the regulatory domain of RIG-I. The interest of this is that this regulatory domain is also the binding site for the PAMPs such as the HBV RNA that is -- results in the activation of IRF-3 and our hepato-selective innate immune response.

As you all know, we've also demonstrated extensively in our preclinical models that inarigivir up regulates intrahepatic RIG-I selectively, activates intrahepatic ISGs, and this activation results in the suppression of all of the features of hepatitis B, including surface antigen, DNA, RNA and cccDNA in the woodchuck model.

We now have further clinical evidence from our HBV trials for the activity of inarigivir as an immunomodulator. First of all, I'll remind you that in hepatitis C, our studies showed that inarigivir was a potent antiviral against HCV with a maximum 2 log reduction within the first 7 days and that this response was proportional to ISG activation in peripheral blood mononuclear cells and the IL-28b status of the individual, which is predictive of the innate immune response in an individual. Thus, we're seeing responses with inarigivir according to the innate host immune response.

Our preliminary data that we've generated now shows that inarigivir responses in HBV are also associated with markers of immune activation, including the down regulation of IP-10, which is a feature associated with clearance in both HBV and HCV in patients on interferon therapy and also preliminary evidence of activation of ISGs in peripheral PBMCs from patients treated with inarigivir. This would result in a two to fivefold increase in ISGs in the PBMCs.

Finally, we've also reported data from our collaborator, Dr. Locarnini in Australia, showing the importance of inarigivir as an activator of the B cell neutralizing hepatitis B surface antibody response, which is seen in HBV responders from our clinical trial. This data overwhelmingly shows the importance of the immune regulation that inarigivir shows in both HCV and HBV.

I also want to just remind you of the study design of Part A of the ACHIEVE trial. We have previously reported the 25- and 50-milligram doses, and here today, we will discuss both the 100-milligram dose and the cumulative data of all the first 3 cohorts. As Marty told you, the 200-milligram cohort is almost fully enrolled, and we expect to -- anticipate full enrollment in the next few weeks.

The treatment duration is 12 weeks for inarigivir monotherapy followed by a switch to tenofovir disoproxil or Viread 300 milligrams daily. Primary endpoint is safety and HBV DNA reduction with multiple secondary endpoints that are being determined, including HBV RNA, surface antigen, e antigen and core-related antigen.

This is the demographics of the HBV population that has been studied so far in the inarigivir trial. I would like to point out to you that this is a global real-world HBV patient population, unlike some of the data that we have seen from other clinical trials in this space. In particular, you can see that the genotype distribution is reflective of the real genotype distribution of a majority of HBV patients in the world, in particular with a significant proportion of patients with genotype B and the harder-to-treat genotype C patients.

You can see here that each cohort consists of approximately 20 patients and that those patients are randomized 4:1 to active drug versus placebo. What we've done here is divided the patients according to both dose, so the cohort 1 is 25 milligrams and according to their e antigen status, showing the e antigen positive and the e antigen negative patients separately.

As you can see, in cohort 3, there were 17 patients randomized to active drug and 3 to placebo. 13 patients received -- were e antigen positive and 4 patients e antigen negative. The mean ages are proportional, and they tend to be relatively young, a slight gender bias towards males. All patients had elevated ALT at baseline. This was one of the criteria for entry, and the patients are naïve. Most importantly, you can see the significant difference between the mean baseline HBV DNA in patients who are e antigen positive versus those who are e antigen negative, showing that the e antigen positive patients have high levels of HBV DNA. And in fact, in cohort 3, this was the highest cohort we saw, with a mean of 8.2 logs for the HBV DNA.

Now turning to our results. And these results will, again, be presented in the fashion of the HBe-antigen positive patients first, followed by the HBe-antigen negative patients. This is looking at the DNA response in HBV e antigen positive patients, looking at the comparison of DNA response to placebo. And here, we're looking at it according to the actual e antigen positive placebo patients, so that it's really reflective of what we see.

As you can see, there was a dose response with inarigivir at 25 milligrams. There was really no clinically significant difference between patients on placebo and those on inarigivir, and this is increased at the 50- and 100-milligram dose. For the first time also in the 100-milligram group, we're beginning to see a significant difference in patients with HBV RNA reductions on those that are receiving the 100 milligrams of inarigivir.

The results are really much more striking in the e antigen negative patients. This, again, is data at Week 12, the end of the inarigivir monotherapy, compared to placebo. What you see here is a significant dose response in HBV DNA response from 25 to 50 to 100. Maximal reductions at 100 milligrams were 2.76 logs for HBV DNA, which is comparable to the other oral agents in development.

I would like to remind you that we are still at an extremely low dose of inarigivir. We have gone up as high as 800 milligrams in hepatitis C patients. And in addition, we have shown good responses at these low doses.

The HBV RNA response parallels very much the HBV DNA response, as one would expect and completely different from what one sees with Nuc therapy. I have here combined the patients with the 50- and 100-milligram dose simply because, of the patients who received 50 and 100 milligrams, 5 patients actually started off with undetectable HBV RNA, so it's very difficult to get enough power without combining the 2. But again, you can see a significant reduction in the combination of the 50- and 100-milligram arms, and you see an average reduction of about 2.9 logs, which is very similar to what we're seeing in terms of the DNA response. We are very pleased with the response of e negative patients.

Now one of the issues is why is there a differential response and is it really based on e antigen status. This resulted in us evaluating the response in terms of baseline surface antigen. Bear with me for a moment. This is a little complicated slide. What this is doing is it's taking all of the patients that were treated with inarigivir and dividing them according to baseline surface antigen. We divided baseline surface antigens as those with surface antigen less than 10,000, or 10 to the 4, logs and those greater than 10,000. When we did this, you can see that 16 of the 17 e negative patients had a surface antigen of less than 10,000 and also 10 of the hepatitis B e antigen positive patients.

Here, we plot the individual patient data showing the mean and the 95% confidence intervals, looking at HBV DNA and HBV RNA decline. What you see here is a highly significant prediction of the response to inarigivir according to the baseline surface antigen levels of less than or greater than 10,000. This is very interesting because it's what one would expect from an immunomodulator. The HBsAg is a strong predictor of down regulation of the immune response, and therefore, we feel that this is important data for understanding the MOA of our drug. Also interestingly, the majority of patients in our trial so far have actually had surface antigen levels of less than 10,000, in particular, in the e negative patients.

Just looking at the summary of the Phase II data from all cohorts with the effect on surface antigen, I'd like to show you some of the data that we've generated and then compare this to what is known from both the literature and recent clinical trials. First of all, we are the only oral drug, I believe, to demonstrate meaningful clinical significant effect on HBsAg and meeting our predefined endpoint of a 0.5 log reduction.

I would remind you that the reason the 0.5 log reduction was chosen as clinically meaningful is that this is the level at which you have a prediction of failure to respond to interferon. Our drug has multiple effects besides the interferon releasing effect, but we felt that, that was the only drug that we could really compare to in terms of an effect on surface antigen.

When we compare it to interferon, interferon monotherapy has a 15% response rate with this 0.5 log reduction, and we already have demonstrated 28% response rate with 13 of 47 patients experiencing this 0.5 log reduction on inarigivir alone or after the switch to tenofovir. Our mean reduction is 0.8 logs, and the range is from 0.5 to 1.4 logs in the 13 responder patients.

The effect on HBsAg is seen at all doses, and it's seen in both monotherapy and also seen after the tenofovir switch. In fact, interestingly, patients who are responding to monotherapy but cannot sustain that response when they switch to tenofovir have a potentiation of the response and therefore, become responders.

The surface antigen response is seen in 7 e positive and 6 e negative patients, again, demonstrating that it's the baseline surface antigen level and not the e status but is really the most important aspect. And it is also seen across all genotypes, which we would expect as this is a host immune modulating agent.

Let us put this into perspective of where inarigivir is compared to other approved or investigational oral HBV drugs. Inarigivir has this response of 28% reduction in HBsAg. Contrast this to the studies on Vesatolimod, the TLR-7 agonist, at the highest dose of 4 milligrams daily. Here, the Week 12 mean reduction was 0.05 logs, certainly much less than we have demonstrated with inarigivir. No patient had a 0.5 log reduction.

Let's compare this to tenofovir/TAF. Here, we have data on the Week 48 mean reduction. For e antigen positive, this is 0.3 logs. For e antigen negative, it's 0.017 logs, with an overall less than 1% of hepatitis B surface antigen loss.

Finally, let's evaluate the cPAMs or CAPSIDs. And to date, we have had no effect reported on surface antigen up to Week 4. Interestingly, with inarigivir, the effect is seen within the first 4 weeks.

So now to turn to our clinical collaboration with Gilead. This has been a very interactive and interesting clinical collaboration. We are happy to be part of the development plan of HBV therapy with Gilead. They have, as you know, expanded their Phase II HBV trial. In discussions, we have decided together that the 200-milligram dose with Vemlidy would be the most appropriate dose to look at in terms of combination therapy in both e antigen positive and e antigen negative patients. And this cohort has been added.

We're also going to be looking at adding a totally new cohort in virally suppressed patients. We feel that this is very important both for us to understand the effect of inarigivir in the virally suppressed patients but also to see which particular immune profiles are activated in virally suppressed patients, giving the potential for dual immunotherapy trials.

Now let me turn to some of our development plans. Our development plans are really focused on having the broadest development in terms of looking at multiple trials that account for the heterogeneity of HBV. We have divided our populations up into the e antigen negative and e antigen positive patients simply because we have the ability to study these patients in separate clinical trials.

Let's just remind ourselves about the global HBV situation. In e antigen positive patients, this accounts for the majority of HBV patients, 70% to 80%. It's certainly the dominant population in the U.S. and EU. It tends to be a slightly older age group because the change from e pos to e neg happens over time. And these patients tend to have a lower viral burden as determined by HBsAg, as we showed in our clinical trial.

The e antigen positive patients, obviously, are younger. They have a higher viral burden. And most interestingly, this group has actually been reduced because of the global uptake of vaccination strategies. So we believe that the real clinical problem results in the e antigen negative patients. In addition, when you look at our patient population currently under treatment, most patients under treatment for long-term continuous treatment are e antigen negative.

Let's look at the U.S. and EU, where we have 17 million patients that are infected and treatment rates that approach 10% to 15%. We have decided that the Nuc-suppressed population give a very good opportunity for the evaluation of inarigivir, and here, there is the potential for inarigivir monotherapy with a rapid pathway to approval. We have 2 trials that we'll discuss with you. One is called Stop & Shock, and the other one is called Suppress & Shock.

We also believe that our new combination drug, SB 9225, which is a combination of inarigivir plus tenofovir, has a great opportunity to increase treatment rates, particularly in HBV naïve patients, and we will be exploring this in the second half of next year. Finally, we realized that there are multiple drugs in clinical development. Our goal is to be a backbone agent as an immunomodulator that's safe, simple and effective and orally administered.

As you know, we have previously announced collaborations with Arrowhead, and we hope to continue with their new ARO-HBV product in combination with either SB 9225 or maybe even inarigivir alone. Finally, drugs with other mechanisms of action are also of interest to us, and we continue to be in discussions with various potential partners.

Let us turn to some of our own trials. First of all, Stop & Shock. Stop & Shock is based on the concept that, so far, the best results that have been reported in terms of surface antigen loss are when one takes long-term virally suppressed e negative patients and stops the Nuc. After stopping the Nuc, there is the evidence of virus reemergence, which usually occurs within the first 4 weeks. This viral reemergence can reactivate the host immune response, as determined by minor ALT flares and increases in IP-10 that result in anywhere from 10% to 20% of patients experiencing durable surface antigen loss. This data has been generated predominately from Europe and Asia, and it is actually approved under the EASL and APASL guidelines to do this type of therapeutic stop.

With inarigivir, since it is so simple, safe, effective and without side effects to date, the idea is that once stop has occurred and the virus begins to emerge from the body, that a simple shock takes place. Shock is -- should be in little letters because we're not doing a big shock. It's just a little shock, a little immune shock that will reactivate the host immune system and result in increasing potentials for viral clearance. We anticipate that there is data on interferon in Asia that shows that up to 35% of patients can actually be treated by interferon after Nuc-suppression or while on Nuc-suppression and result in surface antigen loss. There is the potential here to really reach clinically meaningful significant loss of surface antigen in the large global e negative population already on treatment.

Let's turn to Suppress & Shock. Here, the concept is that there are patients who are already Nuc-suppressed that would -- should remain on Nuc therapy. Here, the idea, again, is to use inarigivir to shock the immune system into activation. After long-term Nuc-suppression, many patients actually have relatively low levels of surface antigen, and this appears to be a good target population for inarigivir. The expansion of the Gilead clinical trial into suppressed patients helped us to accelerate our plans here for this Suppress & Shock philosophy, and we will have data generated, hopefully, in the near future, which will show that this strategy to promote durable surface antigen loss is appropriate.

Turning to our fixed-dose combination. Our goal is to launch naïve trials in HBV patients in a global fashion in the U.S., EU and Asia starting in the second half of 2019. These will be newly diagnosed chronic HBV patients. We will compare inarigivir for 24 weeks to tenofovir alone. The primary endpoints will be DNA and durable surface antigen loss. And then I've spoken to you about our proposals for addressing the high viral burden population potentially with combination trials moving forward.

Just to show you the overall development plan, we're now coming to the end of our own ACHIEVE Part A trial for the dose finding and have shown excellent results to date. The Phase II Gilead study is ongoing and expanding, as we have informed you.

And this is just a time line of our studies. Stop & Shock, we hope to launch in Europe by the beginning of '19; Suppress & Shock, sometime at the end of the first quarter, and this will include a U.S.-based cohort. And the Gilead clinical trials with Vemlidy in virally suppressed are already ongoing. And then our goal is to start looking at novel combinations and SB 9225 in the second half of 2019.

So let me give you a summary of the ACHIEVE trial and our clinical program to date. We have certainly no evidence of any significant side effects. Patient convenience and safety are critical to success in HBV. Inarigivir remains a once-daily oral therapy, and it has a demonstrated -- a continuing favorable safety profile in the clinic. And just to put this into perspective, overall, we have treated now just about 100 patients, approximately, in doses up to 900 milligrams.

Dose-dependent responses were reported for cohort 3 to date; maximum reductions in DNA, 2.76 logs; RNA up to 5 logs. The majority of e negative patients are negative by the end of 12 weeks with respect to HBV RNA. We have a 28%, the highest reported responder rate for surface antigen decline across all 3 cohorts. We have continuing evidence of immune activation by inarigivir in HBV patients, and as you know, most experts agree that a functional cure to HBV will require immunomodulation both in terms of achieving this and also in terms of shortening the potential duration of therapy, 2 goals for which inarigivir is being developed. And finally, we're happy that we are continuing to expand our clinical collaborations with the Gilead Sciences.

Let me now turn this call back to Marty. Thank you very much for your time.

Thank you, Ned. So when the operator gives us the signal, we'll take questions -- some questions from the audience.

(Operator Instructions) We will now take our first question Ted Tenthoff of Piper Jaffray.

Really encouraging. Ned, I was wondering if you could expand a little bit more on the evidence that you've generated demonstrating inarigivir is working as an immunomodulatory agent.

That's a really good question, Ted. So first of all, I think we have to go all the way back and look at our scientific evidence. So inarigivir itself, this small dinucleotide, has no effect on HBV or -- and so it only works in the presence of RIG-I. So what we've been able to show is, most recently, where it binds to in RIG-I, and it binds to the regulatory domain, the same domain that recognizes PAMPs and activates RIG-I. SO you now see that it activates it. We've demonstrated that if you knock down RIG-I in cells, there is no activation. So you have to have RIG-I present. And we've demonstrated that the antiviral response is proportional. We've shown the same thing in the woodchuck even in better ways because it's a in-vivo model. Then, we go to our hep C patients. Here, the data is overwhelming. There is no direct acting antiviral response of inarigivir against HCV. It doesn't interact with the RNA of HCV. But what we have shown is that, here, the proportional reductions in virus are related to the IL-28b status, which, as you know, is -- tells you whether somebody is interferon sensitive, so it works best in CC patients. And secondarily, we've shown that it's associated with activation of ISGs in PBMCs. Now, in the inarigivir HBV trials, we've demonstrated preliminary some of the same things: activation of ISG15. That's the key interferon sensitive gene in PBMCs in responder patients. We have shown an association between serum IP-10, again, a marker that's present for both HBV and HCV patients that indicates activation of immunity. And so all of these things point that the mechanism of the action of RIG-I is through activation of the innate immune response. We call it a selective immunomodulator, and I'm pretty comfortable that, that's the primary mechanism of action.

That's really helpful. And one other quick, if I may. I was really interested to see the results in the e antigen negative patients, but then your commentary that this may not actually be what's driving that. So as you guys go forward into additional studies and combo studies, will you be selecting for e antigen? Or not necessarily?

No, I think we'll be looking very carefully, and we will have some specific e antigen negative studies. So Stop & Shock is e negative, in particular, because it's designed as an approach to the e negative patient. I think that the issue that we've demonstrated is that viral burden is important for activation of immunity. And this has been known for a long time. The more virus there -- viral particles there are and surface antigen, the less of an active immune response you have. And so we're hoping that, in fact, some of our therapies with our potential collaborators will actually be looking specifically at high viral burden patients. And we've explored these issues with a number of companies, and it's a good rationale, potentially, for our planned collaborations with Arrowhead, because what they do is they reduce the surface antigen. What we do then is gently turn back on the immune response.

We will now take our next question from Katherine Xu of William Blair.

I wonder, would you disclose at this moment the baseline surface antigen levels?

So you can actually see that from the surface antigen slide. Well, you can see the numbers of patients. So the baseline surface antigen levels in the e positive, the mean is around 10 at -- is about log 5, so it's around -- between 10 and 100,000. In the surface antigen negative patients, 16 of the 17 are less than 10,000. So it's actually a typical distribution. These patients are -- I can't stress this enough. This is not like one of the cPAMs, which was all genotype D patients with low viral load. This is an absolute reflective population of global HBV. So you've got genotypes A, B, C and D. You've got high viral load patients. You've got the [tau] (inaudible) spectrum. You've got e pos, e neg. The only thing that's not reflected in this population is the presence of cirrhosis since, by definition, these patients are noncirrhotic.

So you don't really -- so in terms of an s antigen response, from this perspective, you don't really see a dose response, right? So I see you have a few in the 25, 1 in the 50, and then you have a few in the 100s.

I think we have something like 7, 2, 4, which accounts for 13. And in fact, this is perfectly reflective of what one would expect to see with surface antigen responses. Remember, the -- when we're dealing with the immune response, it's not necessarily the same in all patients. In fact, there's both viral parameters that are important here, and there's also host parameters in terms of immune activation. This is why this is so clearly an immunomodulator. And in fact, what you see is that the patients who have so-called easy-to-treat genotypes, A, for example, and B, are the best responders. And then you see some response in C, which are the harder-to-treat patients and genotype D, of which we don't have very many. So this is -- to me, this is actually very favorable. It allows us to choose our dose based on all of the different parameters. So we can look at this and say, well, HBV RNA reduction is an added benefit to the Nuc. HBV RNA reduction doesn't occur with Nucs. In fact, it goes up. And then we can look at this and say, well, we're going through a different mechanism. You'll see at AASLD our new trial that shows exactly where the direct acting antiviral effect of inarigivir occurs, and you'll see that it is not a capsid inhibitor. It is not an encapsidation inhibitor, but its effect is upstream of the Nucs. Thereby, just like the cPAMs say, we can add to the Nuc therapy, guess what? Our 2.76 log reduction in DNA and 5 log reduction in RNA can so-called add to the Nuc therapy. But also, we will be immunomodulating the patients, thereby adding further benefit.

Right. And then with the Gilead 200-milligram expansion cohort, do they need to start that cohort after your own monotherapy arm carries some results on the safety and efficacy?

So it's not an issue with efficacy. It's -- the regulatory authorities have asked us to give them the data of our own 200-milligram dosing cohort prior to the (inaudible).

(inaudible) preliminary 12-week safety -- is that with preliminary 12-week safety (inaudible)

Yes. But Katherine, they can move forward with the 100-milligram inarigivir in the Nuc-suppressed population here very shortly.

Yes, okay. And then do you plan to go up to 400 (inaudible)?

I want to stress -- Katherine, sorry. Sorry, sorry, Katherine. I want to stress that this is Gilead's clinical trial and not Spring Bank's clinical trial. So these decisions are made by Gilead.

Yes, yes. Do you eventually plan to go up to 400 to explore higher monotherapy?

We -- since we have such a favorable safety profile, we will go to 400 milligrams. It is part of the dosing strategies of our Phase IIb trials that I showed you, so we will do that. We won't do it in the ACHIEVE trial because we think we can do it faster in the new trials that we're launching.

Right. And then finally, Stop & Shock versus Suppress & Shock. So for Stop & Shock, you already have some potential safety issues. Some of these people might flare up, and you have to really follow them carefully. So I wonder, for e negative patients, why not also do just a Suppress & Shock. This way, at least from a safety and monitoring perspective, it may be easier. I'm just curious. And then why would you think, let's say, with e negative patients, Stop & Shock will be better than Suppress & Shock?

So I think that if you look at both populations, they both represent great opportunities for us. So these -- both Suppress & Shock and Stop & Shock are predominantly in e negative. So Stop & Shock is all e negative, and Suppress & Shock will be predominantly e negative or e positive patients that have recently converted to e negative. And both of these strategies have very strong rationales. Stop & Shock is of great interest because it's a very quick pathway to approval and registration. You should -- we should really be able to get an effect very quickly in that trial. Suppress & Shock is also going to be predominantly in e antigen negative patients since those are the most chronically suppressed patients that we have in the U.S. And in Suppress & Shock, it's kind of like what you're looking for with the add-on to interferon, where the results are quite variable. Some studies show small improvements. Other studies show up to 30% of patients losing surface antigen. So we will explore both. But the purpose of doing it in this fashion is a 2 beat, really, because we feel that there is a role, potentially, for even another drug to be combined with us. So we like the concept of not just using a hepato-selective immunomodulator like inarigivir but also to consider whether there is a potential role for an alternative-type adaptive immunomodulator that could be used in combination. So we're always thinking ahead in terms of where are we going to be down the line. I think it's naïve to think that any one drug is going to cure HBV in a significant proportion of patients. I think that one has to be prepared for both the concepts of multi-drug regimens safely given and also for the concept of seeing how multi-drugs can shorten the duration of therapy potentially rather than slow dual-combination therapies. It's just a -- that's a personal scientific bias.

(Operator Instructions) We will now take our next question from Liisa Bayko from JMP Securities.

Jon on for Liisa. Congrats on the progress. Just a couple. When you guys give us the s antigen reduction for the responder patients, I was wondering if you'll have the overall s antigen reduction for all patients, all 47?

I don't have it off the top of my head, but if you want a mean number, it's somewhere between -- it's somewhere around 0.35, 0.4 logs. That's the mean overall for this -- for the entire 47-patient population.

Great. And of the 3 patients who hit that 0.5 log reduction in the third cohort, do you know whether that was at Week 12 or Week 24 after tenofovir?

It's both.

So they're at 0.5 at Week 12 and then the same 3 were at above 0.5 at 24. Is that correct?

No, no. So 2 of the 3 were at 0.5 at Week 12, and one was at 0.5 after Week 24, as far as I can remember.

Great. And just one last question. I saw recently that they had...

And -- sorry. Sorry, all of them -- all of these responders are -- have a continued response. So they don't rebound. Or let me put it this way, very few rebound after the switch to tenofovir, very, very few, all right? So most of the time, the response is an ongoing type response.

Got it. And FDA recently put out an updated surrogate list, and for hepatitis B, they've said a surrogate they want to see is HBV DNA. Can you just comment on kind of your thoughts on what -- why they'd want to see DNA as opposed to s antigen, which has kind of been the focus for everybody in development today?

So I think this is the traditional pathway. So if you think about FDA and HBV, they started off with approval for liver biopsy improvement of histology. Then, they went to more virological endpoints, and DNA was the endpoint. So when they're saying this, to have an antiviral effect and why it's our primary endpoint in ACHIEVE, you have to show DNA reduction. So if you think about it, everybody talks about DNA reduction unless they're dealing with suppressed patients. So for example, the cPAMs are focused almost entirely on DNA reduction, and they're somewhere between 2.5 and 3.5 log reductions. We, on the other hand, are focused on the newer, more novel and what we think are more relevant endpoints for the scientific community, which is essentially RNA as a surrogate for cccDNA and surface antigen as a surrogate for HBV cure. And also, we have presented previously our HB core data. But I can tell you that we will present our full HBV core data at AASLD, and we will also present our e antigen data, which is very interesting, at AASLD as well. I'm just giving you the highlights. My scientific integrity has to be maintained so that I have new data at these meetings.

We will now take our next question from Madhu Kumar from B. Riley FBR.

This is actually Jennifer on for Madhu. I have just a few for you. The first is, is there clinical data that suggests combining inarigivir with a Nuc will achieve deeper knockdown of surface antigen than inarigivir as a monotherapy? And then a second question, to what extent does the fraction of inarigivir surface antigen responders correspond to the fraction of e antigen negative patients? And...

Okay, those are great questions.

Yes, you can start there.

So the first one is that inarigivir plus a Nuc given together is being done by Gilead. And we cannot discuss their data at this -- at the moment. Interferon plus a Nuc, which is -- we use interferon as a surrogate because it's the only immunomodulator that's approved for HBV. Interferon plus a Nuc clearly has a much more significant response when it's combined with a Nuc. Let me put it into numbers for you, so you can compare it with what we're showing with inarigivir. Interferon monotherapy is around 15%, 0.5 log reduction; inarigivir, 28%. Interferon plus a Nuc at Week 12, 20% surface antigen reduction by 0.5 logs; for us, again, 28%. So already, we're demonstrating with monotherapy superiority to interferon. That response of 0.5 logs at 12 weeks is predictive of whether you go on to clear HBsAg with interferon therapy. Monotherapy clearance rates are somewhere around 3% to 5%, combination therapy with tenofovir around 10%. So the answer to the question is inarigivir plus a Nuc, it's underway. Interferon plus a Nuc, yes, there is an improved response. That's what we base it on. That's where the 0.5 log number comes. That's where we've shown numerical superiority at the moment, all right? The second question about e pos, e neg is, in fact, if you look on one of the slides, it actually set the percent -- the numbers of e pos and e neg. I believe it was 6 e neg responders out of 17 and 7 e pos out of -- no, 6 -- there's a total of 17 e neg patients. So it's 6 of the total 17 e neg patients responded, and 7 of the total 32 e pos patients responded.

And then just to follow up with that, in the Suppress & Shock trial, do you plan to screen for the 12 week -- screen at 12 weeks for surface antigen decline before long-term dosing? And if so, would you use the 0.5 log declines as a natural cutoff?

So in fact, it's very interesting. In suppressed patients, when one looks at response, it's actually only a 0.2 log decline at Week 12 that's predictive of response. Again, these people are starting at much lower levels. This is also true in what we call chronic carrier studies, which are very similar to suppressed patients. So a chronic carrier has surface antigen, low levels of DNA, just like a suppressed patient, and normal ALT. And in those patients, when you treat with interferon, again, it's around a 0.2 reduction at Week 12 that's associated with clearance. I think what we're going to look at for both of these studies is exploratory endpoints to get a signal. And we want to get the signal quickly so that we can move into either monotherapy Phase III or else combination therapy Phase -- further Phase IIb. So we will look at both 12 and 24 weeks. That will give us the ability to determine which is the best way to go.

There are no more questions in the queue at this time. I'd like to turn the conference back over to Marty for any closing or additional remarks.

Well, thank you. And thank you everyone for joining us this morning. We're very pleased to give you the progress. We'll continue to keep you informed on our progress. As Ned alluded to, there are several major scientific relevant conferences the balance of this year. We'll be rolling out additional broad data in a series -- on a series of elements related to inarigivir and our HBV program, and we'll be informing you and announcing these events as we move forward through the balance of the year. So I ask you to look forward to that as we come out with even more progress in our program and a more fulsome dataset. So thank you again. We look forward to working with you as we move down the road. Have a good day.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.