Arrowhead Pharmaceuticals Inc (ARWR) 2014 Q3 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Research FY14 third-quarter financial results conference call.

(Operator Instructions)

I will now hand the conference over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead.

Thank you. Good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for its FY14 third quarter, ended June 30, 2014.

With us today from Management, our President and CEO, Dr. Christopher Anzalone; Chief Operating Officer and Head of R&D, Dr. Bruce Given; Chief Financial Officer, Ken Myszkowski. Management will provide a brief overview of the quarter, and will then open up the call to your questions.

Before we begin, I would like to remind you that comments made during today's call may contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934. All statements, other than statements of historical fact, including without limitation, those with respect to Arrowhead's goals, plans and strategies, are forward-looking statements. They represent Management's current expectations and are inherently uncertain. Thus, actual results may differ materially.

Arrowhead undertakes no duty to update any of the forward-looking statements discussed on today's call. You should refer to the discussions under Risk Factors in Arrowhead's annual report on form 10-K, and the Company's quarterly reports on form 10-Q, for additional matters to be considered in this regard.

With that said, I'd like to turn the call over to Dr. Christopher Anzalone, President and CEO of the Company. Chris?

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today.

The fiscal third quarter and recent period have been exciting and productive times for Arrowhead. We continue to push forward rapidly with our product developments and pipeline expansion goals, and now have two drug candidates in or approaching the clinic, and a handful of other undisclosed programs that are progressing nicely. Let's begin with our lead candidate, ARC-520, for the treatment of chronic hepatitis B infection.

I'll provide some highlights, and later in the call, Bruce will provide more detailed information. As you know, earlier this year, we initiated a dose finding Phase IIa study designed to inform a multi-dose Phase IIb study.

Our two primary goals were to identify a dose that, A, induces a 90% reduction of circulating s-antigen after a single administration; and B, provides durable enough knockdown to enable once per month dosing. Given our studies in multiple animal models, we were quite confident that we could achieve these, but just did not know what that dose would be in humans.

Our interim results have been extremely exciting. We completed dosing of 1 and 2 milligrams per kilogram in June, and those studies [double] blinded, several important conclusions may already be drawn. We are seeing clear knockdown in both groups, and duration of that knockdown has been substantially longer than we expected. We currently have data from the 2 milligrams per kilogram cohort, as far out as two months after dosing. And in these patients, we perceive -- and in the patients we perceive as having received ARC-520, we still see substantial knockdown at this time point.

Interestingly, some of those patients may have s-antigen levels that are still declining. Safety profiles in both groups were also at least as good as those seen in the Phase I study.

Because of the favorable safety profiles in volunteers and patients, and because we thought we could demonstrate even deeper knockdown, we decided to explore 3 milligrams per kilogram in patients. We have begun dosing that cohort. We see substantial opportunity to demonstrate deep knockdown, because of the steep dose response curve observed in non-human primates.

We also see limited downside risk at this dose, because we completed a 3 milligrams per kilogram cohort in healthy volunteers, and that safety profile was quite positive, consistent with all other groups tested. We view these emerging data from the Phase IIa study as very important for the HBV field, where, to my knowledge, clear and consistent reduction of s-antigen in humans have never been demonstrated.

These preliminary data are also important in the broader RNAi field, because they suggest a uniquely long duration of activity in humans. This not only speaks to the potential power of ARC-520, but also to that of future candidates built on the DPC platform.

This point, during the quarter, we nominated our second clinical candidates using DPC delivery, ARC-AAT, and hosted an Analyst Day to present pre-clinical data. ARC-AAT is designed to treat liver disease associated with a genetic disorder called alpha-1 antitrypsin deficiency, or AAT.

The disease is characterized by the production of a mutant form of the enzyme alpha-1 antitrypsin, that cannot be properly exported from hepatocytes. The non-mutant form, or native form, of alpha-1 [antitrypsin] protects lungs from inflammation, so AATD causes lung damage due to the lack of the native enzyme in circulation.

It may also cause clinical liver disease, because accumulation of mutant alpha-1 antitrypsin in (technical difficulty) can lead to cirrhosis and hepatocellular carcinoma. It is thought that there are approximately 100,000 people in the US with the most severe form of AATD. And while there are well-established therapies to treat pulmonary sequalae, there are no approved therapies for liver disease associated with AATD.

It is believed that stopping the production of mutant un-exported enzyme will halt the progression of AATD associated liver disease, and reverse prior fibrosis associated with it. For these reasons, we believe this is a substantial unmet medical need that we can address effectively.

We have generated impressive data sets in animal models, and are moving quickly toward the clinic. We are on track to file -- the file to commence clinical studies for ARC-AAT by the end of calendar 2014.

During the quarter, we also announced that we signed an agreement with The Alpha-1 Project, or TAP, the venture philanthropy subsidiary of the Alpha-1 Foundation. Under the terms of the agreement, TAP will provide funding for the development of ARC-AAT, make its scientific advisers available to Arrowhead, assist with patient recruitment for clinical trials, and engage in other collaborative efforts that support the development of ARC-AAT.

That Alpha-1 Foundation is an extraordinarily well organized and sophisticated patient advocacy group, so we view TAP funding as validation for our program, and a gateway to an effective partner for our clinical program and ultimate product rollout.

Overall, we continue to demonstrate rapid and effective execution of our product development programs, and we have clearly made great strides in the recent period. Our clinical data are tracking our field-leading non-clinical data, and I believe we are increasing our first mover advantage in HBV.

Similarly, we are (technical difficulty) in liver disease associated with AATD, and I expect that advantage to continue.

With that overview, I would now like to turn the call over to our COO and Head of Developments, Dr. Bruce Given. Bruce?

Thanks, Chris, and good afternoon, everyone.

For those of us developing new platforms, there is nothing more exciting than taking them into humans for the first time. ARC-520 is that product for us.

As you know, that process started in normal volunteers last year. That study was designed to assess doses up to 2 milligrams per kilogram, and it was reported at the end of last year to show no premature discontinuations, no serious adverse events, similar rate and severity of mild or moderate adverse events for placebo and ARC-520 subjects, and no laboratory or other safety parameters, looking to us or the investigator, like end organ toxicity.

We did note a flushing reaction at 0.6 milligrams per kilogram, and an urticarial rash at 2 milligrams per kilogram, both in ARC-520 treated patients. Those seemed like histamine-related events to us, so we repeated the 2 milligram per kilogram dose, but with pre-treatment with the over the counter oral antihistamine. This dose cohort also went smoothly, and no skin-related AE's were observed.

With this data in hand, we have designed a first in patient study, with chronic HBV patients in Hong Kong, where disease prevalence is high. The protocol doses were 1 and 2 milligrams per kilogram, and this was our first opportunity to not only assess safety and tolerability in patients, but also to assess gene knockdown.

We wanted to isolate HBSAG, or surface antigen, as the parameter of interest. So we conducted this trial in patients negative for E antigen, and our chronic entecavir therapy, with undetectable circulating viral DNA. This is the first report of those results.

As Chris mentioned, the trial is ongoing and still blinded. As in the normal volunteers, the treatment has been well tolerated. There have been no dropouts, and no serious adverse event. The overall rate of AE's has been even lower than in the normal volunteers, and nothing out of the ordinary has occurred.

Safety labs continue to lack indication of end organ toxicity. These patients have received oral over-the-counter antihistamine, and no skin reactions have occurred.

While the trial is still blinded, we have been able to review anonymized profiles for individual surface antigen levels. The 1 milligram per kilogram dose showed clear activity at a modest level. We have surface antigen data for all patients in the 2 milligrams per kilogram dose group through six weeks, and for five of eight patients, we have data through eight weeks.

Again with the caveat that the data are still blinded, we believe that knockdown is clearly deeper in this group versus 1 milligram per kilogram. And at eight weeks, the patients we perceive as having received active drug show surprisingly large reductions in surface antigen. Overall, duration of knockdown appears to be substantially more sustained in humans compared to non-human primates we have studied at the same doses. However, depth of knockdown appears to be similar in magnitude with what we see in non-human primates at the same doses, including the HBV in infected chimpanzee presented at AASLD last year.

We think that we are right around the middle of the ascending part of the dose response curve, at the 2 milligrams per kilogram dose. When the surface antigen data started to emerge, we saw the potential to expand the dose finding study, and explore doses higher than 2 milligrams per kilogram in patients.

In preparation for that, we enrolled a 3 milligrams per kilogram cohort in our still open normal volunteers study. This dose also performed well, without different detected differences from safety and tolerability results at the other doses. Overall AE's do not appear to be increasing in frequency or severity with dose.

With this safety data in hand, as well as from the Hong Kong patients, we amended the Hong Kong study to include a new 3 milligrams per kilogram cohort. This amendment has been approved by both Hong Kong site IRB's, and the study of ESMB also recommended going forward. This cohort is now dosing.

So how should we think about these results? The dose range for knockdown in humans appears to be similar to that seen in non-human primates, including the previously reported HBV infected chimpanzee.

In all of our animal species studied so far, the dose response curve for DPC-assisted RNAi triggers has been steep. Assuming this holds for humans, and we think it will, the 3 milligrams per kilogram dose is likely to give deep knockdown.

Given what we've already seen at 1 and 2 milligrams per kilogram, we would expect that knockdown to be prolonged, well beyond 30 days. And likely, even longer than predicted by non-human primate models. This suggests that we will be able to explore dosing less frequent than once per month in Phase IIb.

We think these data bode well for our upcoming Phase IIb studies, which I want to talk about briefly. Our current plan is to initiate a study in the fourth quarter that will test two dose levels in E antigen negative, anti-antigen positive patients on Entecavir or Tenofovir. It will be a multi-dose, placebo controlled study conducted in the United States, Western Europe and Asia, with a long-term extension.

Our primary endpoint in the extension will be achieving a functional cure in patients, characterized by s-antigen clearance, with or without seroconversion. We consider these our core or anchor Phase IIb studies.

We also plan to initiate a number of smaller exploratory studies in 2015, including various dosing regimens and studies of ARC-520 in combination with immunostimulatory agents. The core Phase IIb and additional exploratory studies aim to provide us with a comprehensive understanding of ARC-520's activity in a broad range of settings, and we believe will allow us to expand our leadership position in HBV.

Let's now turn to ARC-AAT. As Chris mentioned, we have generated impressive non-clinical data.

In animal models, ARC-AAT has been highly effective at knocking down that alpha-1 antitrypsin genes, transcripts, and reducing the hepatic production of the mutant AAT protein. In PIZ mice, which are genetically modified to produce the mutant human AAT, ARC-AAT induced a greater than 95% reduction in circulating AAT levels after a single dose.

After eight weeks of treatment, in multiple dose studies, soluble, which is the monomeric, and insoluble, which is the polymeric form of Z-AAT, were greatly reduced in the livers of PIZ mice treated with ARC-AAT. In addition, liver globule burden was substantially reduced from base line levels, in a comparison to treatment with saline, which showed progressive globule formation.

In primate studies, which as discussed earlier, appear to be predictive of the response in humans, knockdown of AAT in serum persisted for over 10 weeks, with greater than 80% knockdown still observed at the six-week time point. Keep in mind that AAT is produced extra-hepatically, as well. And ARC-AAT only targets that AAT which is produced in hepatocytes.

So what we observed likely translates into multi-log knockdown in the target hepatic cells. We've initiated the final steps required to file for our initiation of human dosing, including necessary toxicology studies.

With that update, I would like to turn the call over to our CFO, Ken Myszkowski, to review our financials for that period. Ken?

Thank you, Bruce, and good afternoon, everyone.

As we reported today, our net loss attributable to Arrowhead for the three months ended June 30, 2014, was $11.6 million, or $0.22 per share, based on 51.9 million weighted average shares outstanding. This compares with a net loss attributable to Arrowhead of $6.1 million, or $0.23 per share, based on 26.1 million weighted average shares outstanding, for the three months ended June 30, 2013.

Total operating expenses for the three months ended June 30, 2014, were $12.7 million, compared to $6.4 million for the three months ended June 30, 2013. Research and Development related expenses were $6.4 million, while G&A costs were $1.6 million. The increase in operating expenses, compared to the prior-year period, are due to the ARC-520 clinical trial, related ongoing toxicology studies, and drug manufacturing costs, in preparation for Phase II clinical trials.

Additionally, last year -- or last quarter, we nominated ARC-AAT as a clinical candidate, and have incurred costs related to pre-clinical toxicology and manufacturing as we prepare to enter the clinic. We expect these expenses to continue to increase, as ARC-520 enters Phase IIb, a much larger clinical trial, and as ARC-AAT enters the clinic.

In addition to outside costs related to clinical trials, operating expenses increased due to higher headcount, primarily Research and Development personnel, as compared to the prior year.

Net cash used in operating activities for the first nine months of FY14 were $24.5 million, compared with $13.6 million in the prior-year period. The increase in cash used in operating activities is consistent with the change in operating expenses.

Turning to our balance sheet, our cash balance at June 30, 2014, was $138.3 million. Including short- and long-term investments and fixed income securities, our cash and investments balance was $188.5 million at June 30, 2014, compared to $29.8 million at September 30, 2013.

The increase reflects the financings completed in October 2013 and February 2014. Additionally, the Company received cash inflow of $12.4 million from the exercise of stock options and warrants.

Our common shares outstanding at June 30, 2014, were 52.9 million, and there were also 21,000 shares of preferred stock outstanding. These preferred shares are convertible in to 5.6 million shares of common stock. Common shares outstanding, including the conversion of our preferred shares, would be 58.5 million.

With that financial overview, I will now turn the call back to Chris.

Thanks, Ken.

We've begun a very exciting phase, characterized by the transition from a science-based company that is full of promise, to a drug company providing real benefits to patients. Until now, we had demonstrated exciting data in animal models, some of the most dramatic in the field, and a good safety profile in healthy human volunteers. We are now taking the next leap forward with ARC-520, by expanding the emerging positive safety profile in more patients at a higher dose, and generating knockdown data in patients.

We are seeing unexpectedly durable knockdown in humans, reinforcing our belief that DPC is our best in class delivery for RNAi, and suggesting that ARC-520 may ultimately be dosed less frequently than monthly. We are also seeing depth of knockdown that is similar to that predicted in animal models. This suggests that primates, and indeed mice, are good models for predicting dose and effect for patients for our technology.

This is a critical insight that we expected, but could only confirm by observing knockdown directly in (technical difficulty) subjects. This allows us to move forward with our entire R&D program, with greater confidence and speed.

Our newly disclosed ARC-AAT program continues to move forward as expected, and the ARC-520 human data validate and de-risk it. We have executed on our goals during the quarter, and are committed to continuing that in the periods ahead.

Some of our upcoming goals include the following: We will present additional clinical data on the Phase IIa study of ARC-520 around AASLD this year, and additional non-clinical data on ARC-AAT (technical difficulty) Press Release, and at key scientific and medical meetings in the fourth quarter. We'll file in the fourth quarter to initiate first in man studies for ARC-AAT. Also in the fourth quarter, we plan to initiate the core Phase IIb studies for ARC-520.

Throughout 2015, we plan to initiate multiple pilot or exploratory clinical studies of ARC-520 to look at dosing schedules and combinations that may improve cure rates. Also in 2015, we intend to nominate one or more additional clinical candidates, which we will talk about more in the future.

So as you can see, we're working on a lot of projects that we believe will add substantial value in the long term, as well as the near term.

I would now like to open the call to your questions. Operator?

(Operator Instructions)

Michael Yee, RBC Capital Markets.

Good afternoon. Thanks, guys. A couple questions. First, on your ongoing Phase 2a study, you qualified the 1 milligram and 2 milligram curves. People are implying that it's -- 2 milligrams is around 0.8 log reduction, like the animal studies. But how -- what is your confidence that 3 milligrams is going to be greater than 0.8? Are you just comparing the current time points in the drop (technical difficulty) -- the time points in the 2 milligrams? How confident are you that that will be greater than 1 milligram. Excuse me -- 1 log?

And then going forward, since you're trying to ultimately get functional cure in the Phase 2b study, how confident are you in functional cure, if you are not above 1 log? And how many doses will you get? And at what time points are you looking at here to actually look at the functional cure?

Sure, let me take a crack at that, and then I'll hand it over to Bruce, as well. Regarding our confidence level in achieving a log knockdown with 3 milligrams per kilogram, we feel pretty good about that.

The -- what we saw in the 1 milligrams and 2 milligrams per kilogram, is that the depth of knockdown seems to track reasonably well with non-human primate models. But of course, the durability of effect is substantially longer. And so that gives us good confidence that 3 milligrams per kilogram will give us good, deep knockdown.

But ultimately, we just don't know until we're in humans. And the fact of the matter is, this is a dose finding study. And so from my perspective, I really don't care what the dose level is that gets us that goal, as long as we get there safely.

And it looks like we have plenty of room, in terms of safety. We haven't seen anything that has been concerning in any of the groups. And so, if we needed to go to 4 milligrams per kilogram, for instance, we think we've got plenty of room to do that.

In fact, to ensure that we've got -- that we can do that in a timely fashion, we decided to go ahead and initiate a 4 milligrams per kilogram group in healthy volunteers, which we may or may not use, to move into 4 milligrams per kilogram in patients. But it's a good thing to have, we figured.

Regarding our confidence in achieving a functional cure, that is the fill in the blank number of dollars question. We are, for good or for bad, pioneers in this field. We are doing something now -- in fact, we have already done something now the world has never seen, which is deep and sustained knockdown, and consistent knockdown, of s-antigen in humans.

So, that's the first hurdle that we appear to be getting over right now. And now, we'll be testing the theory that our KOL's, and frankly, the vast majority of KOL's that we speak with, believe to be true. Which is, if you knock down s-antigen, you can enable the immune system to come back up and clear the virus. We will see that. I suspect that we'll start to -- if in fact this drug works as we all hope and expect it does, I expect that we could start to see some functional cures in 2015. But again, that's just speculation, and only time will tell.

Bruce? Do you have anything? Anything you want to add on that?

Yes, just a couple fine points. Michael, thanks for your questions, and good questions, as always. First of all, what do we expect to see at 3 milligrams per kilogram? Will we say a log as a number? It's a little bit hard to say.

The one thing that we can say is that, with all of our RNAi programs, across mice, rats, primates, the one thing that we have consistently seen is a very steep dose response curve. Frankly, having been in the industry a long time, these are the steepest dose response curves I've ever seen. And I think it just has to do with the catalytic nature of risk, and how the process works.

But from my perspective, if in humans, it is similarly steep, then I think we're going to be in good shape at 3 milligrams per kilogram. If, as Chris said, if it's a little bit more shallow in humans, and we just don't know yet, because we only have 2 points. It's not enough for a curve.

But if it's a bit more shallow, we could wind up having to go to 4 milligrams per kilogram, and that would be fine with us. But if we're as steep as we've seen in primates and other species, the chances are pretty good that 3 milligrams per kilogram gives us what we have been looking for. That's item one.

Item two, just to be a little more specific. The Phase 2b core studies are designed to last 12 weeks, and then patients will roll into an extension. And that extension will take patients out to somewhere around a year of therapy.

We don't know if the theory is correct, that you need to de-repress these patients by reducing surface antigen. We don't know how long therapy needs to be for that to work. And because of that, it's hard to say. As Chris said, we would hope that, in the second half of 2015, that we'll have some patients that have been on therapy for over six months at that point.

And if the answer is, with the kind of reductions in surface antigen that we're providing, if six months or so is long enough for the body to come back, we could start seeing some functional cures. If actually it is less, we could see them earlier. And if it is going to take a full year, or if it's even going to be a little bit like interferon, that -- you de-repress it, and then it takes a little bit of time to come back, it could be a little longer. We just don't know, Michael.

Got it. Do you keep dosing them, and you keep checking on them?

We keep dosing them, and we keep checking. And in the long-term extension, the primary endpoint is, as we've currently designed in a way (technical difficulty) things can always be a little bit fluid. But our current thinking about the principal, the primary endpoint, would be that it will be s- clearance. With or without seroconversion, that that will be the primary endpoint in the extension.

Thank you very much.

You bet.

Alethia Young, Deutsche Bank.

Great, thanks for taking my question, and congrats on the progress. I just wanted to ask about the 1 log theory again. Do you still stand by the 1 log knockdown, if you're seeing a longer duration of response?

And then the second question is, run us through why you believe 1 log is irrelevant (inaudible) time point period right now, when you're basically at 0.8, 0.7 right now? And then I have one follow-up.

Sure. It's a good question. Thanks very much, Alethia. We think that that is an aggressive bogey, in that it is not clear to us that we actually need to reach that level of knockdown. Having said that, we think that we can certainly get there, so we're more comfortable if we have it.

The reason that we have stuck to that, to that bogey, is that the only thing that gives any kind of semi-reliable functional cure is interferon. After a year of interferon, about 10% of patients will reach a functional cure. And all of those patients that do get to that functional cure will see about 0.5 log reduction in s-antigen in 12 weeks, and around 1 log after 24 weeks.

So it's not clear that we need to reached that full log. But we do know that if, at least under interferon therapy, if a patient does not see that sort of s-reduction, then there is no chance they will get to a functional cure. So that's why that feels like a safe zone for us.

Now, we will be seeing reductions in s that are far more rapid than you see in the handful of times that you see it with interferon. And so those difference in kinetics may suggest that we don't need to get a full log. But again, because we can do it safely, we felt most comfortable making that our goal.

Keep in mind, everybody, that the current design has two dose levels against placebo in the Phase 2b. One that we have thought would probably be somewhere in the neighborhood of 0.5 log, and one that would be somewhere in the neighborhood of 1 log. And it is entirely plausible -- any outcome can occur.

Having -- the 0.5 log dose group could do as well as the full log dose group. And of course, it could always turn out that the s-antigen hypothesis is too simple, and that something else is needed, as well.

But the -- both of those groups are serious groups. Those are both serious levels of knockdown. And keep in mind, also, that that is based on what we see at a single dose. Under multiple dose scenarios, entirely possible that there will be continuous step-down in surface antigen levels, as well.

And that may be particularly true in light of the recent data showing that we see a much more durable knockdown in humans that we do --

(multiple speakers) Great, and can I ask my follow-up? Again, with (inaudible), do you think you'll have that data by AASLD? Or do you think we'll be waiting in (inaudible) for that?

No, we believe we'll have it for -- during AASLD. Now, we are hopeful that we will be able to apply for a late breaker presentation, and present it at AASLD. And so if that should work out, then we hope to present it at AASLD. If not, at least we are -- we feel pretty good that the data will come out around that time.

Okay, great, thanks.

Sure.

Thomas Wei, Jefferies.

Thanks. Just wanted to clarify a couple of things that you've said. First, the language in the Press Release, and what you've reiterated on the call about the magnitude of the knockdown being similar to the non-human primate studies. So I guess what I'm a little bit confused by is that, in the non-human primate studies you actually gave two doses, 2 milligrams per kilogram and 3 milligrams per kilogram, on day 1 and Day 15.

So when you're talking about it being similar, for the six patients at 2 milligrams per kilogram who you think are on drug, are you seeing something that around a 0.7 log reduction? Like what the chimp got after two doses? Or are you talking about what the chimp experienced after the single 2 milligram per kilogram dose, before she got her second 3 milligrams per kilogram dose?

Thomas, what -- first of all, we're not just talking about the chimp. We're also talking about generally about what we've seen in non-human primates across a number siRNA. Generally what we feel is that, that 2 milligrams per kilogram dose, if you look across our full experience, tends not to be the maximal dose. Tends to be somewhere in that broad middle range of the ascending part of the dose response curve.

When you get up to 3 milligrams per kilogram and higher, that is when we tend to be up more at the top of the dose response curve. And you start to get into log and even multiple log of levels of knockdown, if that make sense.

So what we're saying is that we're at a part of the dose response curve that's quite easy to differentiate from no knockdowns. But that's not yet (technical difficulty). That's really what we are saying.

We can't be a lot more specific than that, because it is still a blinded study. And we don't know with certainty which two patients in each cohort have received placebo. We think we know who they are, but we don't know with certainty.

And we also -- it also appears that some patients are still declining, in terms of circulating s-antigen. So right now, even if it was un-blinded, it would be premature to talk about peak knockdown, because it's not clear that we [have] reached that.

Okay. But -- so the data that we have -- maybe I don't have a full, complete set of data. But we all have seen the data that you presented at AASLD in the one chimp. And then you're saying there are other non-human primate studies. Do we have the data for those other studies? Or has that not been presented before?

I'm not sure how much of it has actually been published. I think most of it, in one way or another, has probably been presented at places like TIDES. So I am talking about things like Factor 7 and AAT, where we did show data at the analyst meeting that we had at the middle of this year. So there's other data out there.

Recall that, for new world monkeys, HBV does not actually affect new world monkeys. So the only primate data we have for HBV happens to be the one chimpanzee. And as you rightly pointed out, we only have two weeks of data for that chimpanzee at the 2 milligram per kilogram dose. So there, we're mostly talking about the qualitative sense of the knockdown that was achieved there since we didn't follow it long enough, probably, to even get to the nadir for the 2 milligrams per kilogram dose.

Right. It's all going down, then. So you're talking about what would have been predicted if you had been able to follow that chimp out at 2 milligrams per kilogram for longer than 14 days? What you're seeing is better than that? You're seeing what the natural extension of that curve would be, if that had been followed out?

I think it's fair to say that, yes.

Okay. Sorry that I got confused about that. I also just wanted to ask about your commentary around the steepness? So when you keep talking about the steepness of the dose response curve, it sounds like you have a minimal amount of activity of 1 milligram per kilogram. And then you actually have much more robust activity at 2 milligrams per kilogram. So 2 milligrams per kilogram is much more than twice as effective as 1 milligram per kilogram?

Wouldn't want to get into a numbers game. I think, again, that's dangerous for us, in no small part because the data is still blinded. But what we're talking about is the nature of what we've seen across all of these different RNA's that we have studied in all these different species. It's just always struck us that the dose response curve, at least for us, because of -- probably because of the fact that we have endosomal escape, tends to be very steep. From the onset of knockdown to getting very high levels of knockdown, it tends to just be a couple or 3 milligrams per kilogram. It's not a factor of across 10 milligrams per kilogram or something, like you see in some drugs. So it's really very steep, and we have just always been struck by that.

And qualitatively, you're exactly right. When you're on that dose response curve, if you -- you can -- if you double the dose, you substantially more than double the response.

And that -- so you need that curve to continue along better than linear trajectory to meet your target? That's what I should -- I think you had mentioned that earlier during the Q&A, that it needs to continue along that very super-linear steep dose response to get to 1 log?

I think we would say it the other way around. We would just say that, if it behaves the same way as we've seen in other species, we'd feel that the 3 milligrams per kilogram dose should give us very deep knockdown. That's what we're saying.

But everyone wants to put a -- have us put a -- throw a dart at the dart board and say exactly what that knockdown is going to be, that is a little hard for us. But it feels like, extrapolating from what we've seen in other animal models, that 3 milligrams per kilogram should be -- if it's not a goal, it should be very near a goal, would be our expectation. But now, we're getting very forward-looking, when we're going to have the data in our hands, and ready to show people around AASLD.

Okay, great. Thanks. I'll jump back in the queue.

Sure.

(Operator Instructions)

I'm showing no questions at this time. I would like to turn the call back over to Chris Anzalone.

Thanks very much for listening to the call today, and we look forward to providing you additional data going forward. And we will see you at the next call, or at the next meetings.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day.