sb9200电话会议

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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.

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Nezam H. Afdhal, Spring Bank Pharmaceuticals, Inc. - Chief Medical Officer [3]

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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.

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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.