Arrowhead Pharmaceuticals - Earnings Call - Q3 2014

Transcript

Speaker 0

Ladies and gentlemen, welcome to the Arrowhead Research Fiscal twenty fourteen Third Quarter Financial Results Conference Call. Throughout today's recorded presentation all participants will be in a listen only mode. Presentation, there will be an opportunity to ask questions. I will now hand the conference over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Speaker 1

Thank you. Good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for its fiscal twenty fourteen third quarter ended June 3034. With us today from management are President and CEO, Doctor. Christopher Anzalone Chief Operating Officer and Head of R and D, Doctor. Bruce Gibbon Chief Financial Officer, Ken Myszkowski.

Management will provide a brief overview of the quarter and we'll 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 ks 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 Doctor. Christopher Anzalone, President and CEO of the company. Chris?

Speaker 2

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 development 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. Nicely.

Let's begin with our lead candidate, ARK-five twenty 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 2a study designed to inform a multi dose Phase 2b 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 one and two milligrams per kilogram in June. And though the study is still 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 two 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 ARK-five twenty, 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 one 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 three 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 nonhuman primates. We also see limited downside risk at this dose because we completed a three 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 ARK-five twenty, but also to that of future candidates built on the DPC platform.

At this point, during the quarter, we nominated our second clinical candidate using DPC delivery, ARK AAT, and hosted an Analyst Day to present preclinical data. ARK AAT is designed to treat liver disease associated with a genetic disorder called alpha-one antitrypsin deficiency, or AAT. This disease is characterized by the production of a mutant form of the enzyme alpha-one antitrypsin that cannot be properly exported from hepatocytes. The non mutant form or native form of alpha-one antitrypsin protects lungs from inflammation, So AATD causes lung damage due to lack of the native enzyme in circulation. It may also cause clinical liver disease because accumulation of mutant alpha-one antitrypsin hepatosplen can lead to cirrhosis and hepatocellular carcinoma.

It is thought that there are approximately one hundred thousand people in The U. S. With the most severe form of AATD. And while there are well established therapies to treat pulmonary sequelae, there are no approved therapies for liver disease associated with AATD. It is believed that stopping the production of mutant unexported 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 to commence clinical studies for ARC AAT by the end of calendar fourteen. During the quarter, we also announced that we signed an agreement with the Alpha-one Project or TAP, the venture philanthropy subsidiary of the Alpha-one Foundation. Under the terms of the agreement, TAP will provide funding for the development of ARC AAT, make its scientific advisors available to Arrowhead, assist with patient recruitment for clinical trials and engage in other collaborative efforts to support the development of ARCAAT.

The Alpha-one Foundation is an extraordinarily well organized and sophisticated patient advocacy group, so we view TAP funding as validation for our program and 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 nonclinical data, and I believe we are increasing our first mover advantage in HBV. Similarly, we are well positioned leaders 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 Development, Doctor.

Bruce Gibbon. Bruce?

Speaker 3

Thanks, Chris, and good afternoon, everyone. For those of us developing new platform, there is nothing more exciting than taking them into humans for the first time. ARC-five twenty 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 two mgs per kg and 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-five twenty 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 zero point six mg per kg and an urticarial rash at two mg per kg both in our ARC-five twenty treated patients. Those seemed like histamine related events to us, so we repeated the two mg per kg dose, but with pretreatment with an over the counter oral antihistamine. This dose cohort also went smoothly and no skin related AEs were observed. With this data in hand, we designed a first in patient study with chronic HBV patients in Hong Kong where disease prevalence is high. The protocol doses were one and two mgs per kg 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 antigen and on 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 AEs 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've been able to review anonymized profiles for individual surface antigen levels.

The one mgkg dose showed clear activity at a modest level. We have surface antigen data for all patients in the two mgkg 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 one mg per kg 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 the same dose, including the HBV 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 two mgkg dose. When the surface antigen data started to emerge, we saw the potential to expand the dose finding study and explore doses higher than two mg per kg in patients. In preparation for that, we enrolled a three mg per kg cohort in our still open normal volunteer study. This dose also performed well without detected differences from safety and tolerability results at other doses. Overall AEs do appear to be increasing in frequency or severity with dose.

With this safety data in hand as well as from the Hong Kong patient, we amended the Hong Kong study to include a new three mg per kg cohort. This amendment has been approved by both Hong Kong site IRBs and the study 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 three mgkg dose is likely to give deep back down. Given what we've already seen at one and two mgs per kg, we would expect a knockdown to be prolonged well beyond thirty days and likely even longer than predicted by non human primate model. This suggests that we will be able to explore dosing less frequent than once per month in Phase 2b. We think these data bode well for our upcoming Phase 2b 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 and e antigen positive patients on entecavir or tenofovir. It will be 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 curing patient characterized by S antigen clearance with or without seroconversion. We consider these our core or anchor Phase 2b studies. We also plan to initiate a number of smaller exploratory studies in 2015, including various dosing regimens and studies of ARK-five twenty in combination with immune stimulatory agents.

The core Phase 2b and additional exploratory studies aim to provide us with a comprehensive understanding of ARC-five twenty's activity in a broad range of setting 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, AAT has been highly effective at knocking down the alpha-one antitrypsin gene transcript and reducing hepatic production of the mutant AAT protein. In PIC 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 PISC mice treated with ARCAAT. In addition, liver globule burden was substantially reduced from baseline level and in comparison to treatment with saline which showed progressive globule formation. In primate studies, which as discussed earlier appeared to be predictive of the response in humans, knockdown of AAT in serum persisted for over ten weeks with greater than 80% knockdown still observed at the six week time. Keep in mind that AAT is produced extrahepatically as well and ARC AAT only target that AAT that 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 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?

Speaker 4

Thank you, Bruce, and good afternoon, everyone. As we reported today, our net loss attributable to Arrowhead for the three months ended June 3034 was $11,600,000 or $0.22 per share based on 51,900,000.0 weighted average shares outstanding. This compares with a net loss attributable to Arrowhead of $6,100,000 or $0.23 per share based on 26,100,000.0 weighted average shares outstanding for the three months ended June 3033. Total operating expenses for the three months ended June 3034 were $12,700,000 compared to $6,400,000 for the three months ended June 3033. Research and development related expenses were $6,400,000 while G and A costs were $1,600,000 The increase in operating expenses compared to the prior year period are due to the ARK-five 20 clinical trial related ongoing toxicology studies and drug manufacturing costs in preparation for Phase two clinical trials.

Additionally, last year or last quarter, we nominated ARC AAT as a clinical candidate and have incurred costs related to preclinical toxicology and manufacturing as we prepare to enter the clinic. We expect these expenses to continue to increase as ARC-five 20 enters Phase 2b, 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 fiscal twenty fourteen were $24,500,000 compared with $13,600,000 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 3034 was $138,300,000 Including short and long term investments in fixed income securities, our cash and investments balance was $188,500,000 at June 3034, compared to $29,800,000 at September 3033. The increase reflects the financings completed in October 2013 and February 2014. Additionally, the company received cash inflow of $12,400,000 from the exercise of stock options and warrants. Our common shares outstanding at June 3034 were $52,900,000 and there were also 21,000 shares of preferred stock outstanding.

These preferred shares are convertible into 5,600,000.0 shares of common stock. Common shares outstanding, including the conversion of our preferred shares, would be $58,500,000 With that financial overview, I will now turn the call back to Chris.

Speaker 2

Thanks, Ken. We have begun a very exciting phase characterized by the transition from science based company that's 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 ARK-five twenty by expanding the emerging positive safety profile in more patients and at 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 ARK-five twenty 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 predicting dose and effect in patients for our technology. This is a critical insight that we expected, but can only confirm by observing knockdown directly into the subject. This allows us to move forward with our entire R and D program with greater confidence and speed. Our newly disclosed ARK AAT program continues to move forward as expected and the ARK-five twenty human data validate and derisk 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 2a study of ARK-five twenty around AASLD this year and additional nonclinical data on ARK AASD 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 2b studies for ARC-five twenty. Throughout 2015, we plan to initiate multiple pilot or exploratory clinical studies of ARK-five twenty 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?

Speaker 0

Our first question comes from Michael Yee of RBC Capital Markets. Your line is open.

Speaker 5

Yes. Hey, good afternoon. Thanks, guys. A couple of questions. First, on your ongoing Phase 2a study, you sort of qualified the one mg and the two mg curves.

People are implying that it's two mg is around 0.8 log reduction like the animal studies. But what is your confidence that three mg is going to be greater than zero point eight mg? Are you just comparing the current time points in the drug you're seeing, the time points in the two mg? How confident are you that, that will be greater than a mg excuse me, one mg? And then going forward, since you're trying to ultimately get functional care in the Phase 2b study, how confident are you in functional cure if you're not above one log?

And how many doses will you get? And at what time points are you looking at here to actually look at the functional?

Speaker 2

Sure. Let me take a crack at that, and I'll hand it over to Bruce as well. Regarding our confidence level in achieving a log knock down with three mgs per kg, we feel pretty good about that. What we saw in the one point two mgs per kg is that the depth of knockdown seems to track reasonably well with with non human prime models. But of course, the durability of the effect is substantially longer.

And so that gives us good confidence that three mg per kg 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. So if we needed to go to four per kg, for instance, we think we've got plenty of room to do that. And 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 four mg per kg group in healthy volunteers, which we may or may not use to move into four mg per kg in patients, but it's a good thing to have it 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've 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 our KOLs and frankly, the vast majority KOLs 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'll 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 speculation and only time will tell. Bruce, do you have anything you want to add on that?

Speaker 3

Yes. Just a couple of fine points. Michael, thanks for your questions and good questions as always. First of all, I mean, what do we expect to see at three mg per kg? Will we see a log as a number?

It's a little bit hard to say. I mean, 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, this is the 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 human, it is similarly steep, then I think we're going to be in good shape

If, as Chris said, if it's a little bit more shallow and we just don't know yet because we only have two points, it's not enough for a curve. But if it's a bit more shallow, we couldn't wind up having to go to four and that would be fine But if we're as steep as we've seen in primates and other species, the chances are pretty good that three mg per kg 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 twelve weeks and then patient, 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 say. As Chris said, we would hope that, in the second half of twenty fifteen 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 reduction of 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's less, we could see them earlier. If it's going to take a full year or if it's even going to be a little bit like interferon that de repress it and then takes a little bit time to come back. It could be a little longer. We just don't know Michael.

Speaker 5

Do you keep dosing them and you keep checking them? How we

Speaker 3

keep dosing them and we keep checking and in the long term extension, the primary endpoint is, as we've currently designed it, 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.

Speaker 5

Thank you very much.

Speaker 0

Our next question comes from Alethia Young of Deutsche Bank. Your line is open.

Speaker 6

Great. Thanks for taking my question and congrats on the progress. I just wanted to ask about the one log theory again. Just do you still stand by the one log knockdown if you're seeing a longer duration of response? And then the second question is just run us through like why you believe one log is irrelevant both for this time point period right now when you're basically at maybe 0.8, 0.7 right now?

And then I have one quick follow-up.

Speaker 2

Sure. That's a good question. Thanks very much, Alethia. We think that, that is an aggressive bogey and 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 bogey is that the only thing that gives any kind of semi reliable functional cures is interferon. After a year of interferon, about ten percent of patients will reach functional cure. And all of those patients that do get to that functional cure will see about zero five log reduction in S antigen at around twelve weeks and around one log after twenty four weeks. So it's not clear that we need to reach 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 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.

Speaker 3

Yes. Keep in mind everybody that the current design has two dose levels against placebo in the Phase 2b. The one that we have thought would probably be somewhere in the neighborhood of half a log and one that would be somewhere in the neighborhood of a log. And it's entirely plausible, well, outcome can occur. The half a log dose group could do just as well as 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 both of those groups are serious groups. Those are both serious levels of knockdown. And keep in mind also that that's based on what we see at a single dose. Under multiple dose scenarios, it's entirely possible that there'll be continuous step down in surface added levels as well.

Speaker 2

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

Speaker 6

Great. Can I ask a follow-up? Around the three mg per kg dose, do you think you'll have

Speaker 0

that data by AASLD? Or do you think

Speaker 6

we'll be waiting kind of in the 2015 for that?

Speaker 2

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

Speaker 6

Okay, great. Thanks.

Speaker 2

Sure.

Speaker 0

Our next question comes from Thomas Bee of Jefferies. Your line is open.

Speaker 7

Thanks. Just wanted to clarify a couple of things that you said. First, the language in the press release and what you reiterated on the call about the magnitude of the knockdown being similar to the nonhuman primate study. So I guess what I'm a little bit confused by is that in the nonhuman primate studies, you actually gave two doses, two mgs per kg and three mgs per kg on day one and day fifteen. So when you're talking about it being similar, for the six patients at two mg per kg 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 experience after the single two mg per kg dose before she got her second three mg per kg dose?

Speaker 3

So Thomas, you know, first of all, we're not just talking about chimp, we're also talking generally about what we've seen in nonhuman primates, you know, you know, a number of siRNA. And generally what we feel is that that two mg per kg dose, if you look across our full experience, it tends not to be the maximal dose, tends to be sort of somewhere in that broad, middle range of the ascending part of the dose response curve. When you get up to three mgs per kg and higher, that's when we tend to be up more at the top of the dose response curve, and you start to get into the log and even multi log levels of knockdown, if that makes 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 knockdown, but that's not yet. That's really what we're saying.

We can't be a lot more specific than that because it's 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, we don't know with certainty.

Speaker 2

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 unblinded, it would be premature to talk about peak knockdown because it's not clear that we can reach that.

Speaker 7

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 AFLD in one CHIM. And then you're saying there are other nonhuman primate studies. Do we have the data for those other studies or has that not been presented before?

Speaker 3

I'm not sure how much of it's actually been published. I think most of it in one way or another has probably been presented at places like Tide. So I'm talking about things like, Factor and AAT, where we did show data, at the Analyst Meeting that we had in the middle of this year. So there's other data out there. Recall that for, New World monkeys, HPV does not actually affect New World monkeys.

So the only primate data we have for HPV happens to be the one chimpanzee. And as you rightly pointed out, we only have two weeks of data for that chimpanzee at the two mg per kg dose. So there we're mostly talking about sort of 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 two mg per kg dose. Right.

Speaker 7

It's still going So you're talking about kind of what would have been predicted if you had been able to follow that chimp out at two mg per kg for longer than fourteen days. What you're seeing is better than that. You're seeing kind of what the natural extension of that curve would be if that had been followed up?

Speaker 2

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

Speaker 7

Okay. Sorry that I got confused about that. I also just wanted to ask about your commentary around this 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 one mg per kg and then you actually have much more robust activity at two mg per kg. So two is much more than twice as effective as one mg per kg?

Speaker 3

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 that the nature of what we've seen across all of these different RNAs that we've 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 three mgs per kg.

It's not a factor of across ten mgs per kg or something like you see in some drug. So it's really very steep and we've just always been struck by that.

Speaker 2

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

Speaker 7

And 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 and A that it needs to continue along that very kind of super linear steep dose response to gesture log?

Speaker 3

Well, I think we'd say it the other way around. We would just say that if behaves the same way as we've seen in other species, we feel that the three mg per kg dose should give us very deep back down. That's what we're saying. But everyone wants to put a have us put a throw a dart at the dartboard and say exactly what that knockdown is going to be. That's a little hard for us.

But it feels like extrapolating from what we've seen in other animal models, the three mg per kg should be if it's not a goal, it should be very near 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.

Speaker 7

Okay, great. Thanks.

Speaker 0

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

Speaker 2

Thanks very much for

Speaker 3

listening to the call today, and

Speaker 2

we look forward to providing additional data going forward. And we will see you at the next call or at the next meeting.

Speaker 0

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.