Seeking Alpha
We cover over 5K calls/quarter
Profile| Send Message|
( followers)  

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY)

ALN-TTR02 Phase I clinical trial results Call

July 16, 2012 08:30 am ET

Executives

Cynthia Clayton - VP, IR & Corporate Communications

John Maraganore - CEO

Akshay Vaishnaw - SVP & CMO

Analysts

Charles Duncan - JMP Securities

Geoff Meacham - JPMorgan

Marko Kozul - Leerink Swann

Mike King - Rodman &Renshaw

Alan Carr - Needham & Company

Megan Mccloskey - McNicoll Lewis & Vlak LLC

Stephen Willey - Stifel Nicolaus

Operator

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss its Phase I clinical results with ALN-TTR02. There will be a question-and-answer session to follow. Please be advised that this call is being taped at the company's request. I would now like to turn the call over to the company.

Cynthia Clayton

Good morning. I am Cynthia Clayton, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer, Akshay Vaishnaw, our Executive Vice President and Chief Medical Officer and Barry Greene, our President and Chief Operating Officer.

For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the news and investors page of our website at www.alnylam.com. During today's call as outlined on slide two, John will provide some context on the ALN-TTR02 clinical results and what they mean for the program, Alnylam and the field of RNAi therapeutics. Akshay will then review the preliminary results of the ALN-TTR02 clinical study and we will then turn the call over for your questions.

Before we begin and as you can see on slide three, I would like to remind you that this call will certain remarks concerning Alnylam’s future expectations, plans and prospects which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC.

In addition any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent day. We specifically disclaim any obligations to update such statements. I will now turn the call over to John.

John Maraganore

Thanks, Cynthia and welcome everyone and thanks for joining us this morning. To say the least, today is a very exciting day for Alnylam, for RNAi therapeutics and most importantly for patients with transthyretin-mediated amyloidosis or ATTR, a debilitating orphan genetic disease. Before Akshay reviews our new clinical data, I would like to provide some overall context.

Indeed the last 12 to 18 months defined a period of remarkable accomplishments in our scientific and clinical development efforts. Our clinical experience with RNAi therapeutics has grown significantly, with an increasing number of patients or subjects enrolled in clinical studies and in the case of our systemic delivery programs, we have four RNAi therapeutics that have been administered to over 100 patients or subjects with over 330 total doses administered and a length of treatment now exceeding two years. This experience provides us with a growing level of confidence on safety and tolerability, although this experience is still relatively small, but will grow in the future.

In addition, we have now demonstrated positive results in five clinical programs including ALN-RSV for RSV infection, ALN-VSP for liver cancer, ALN-PCS for severe hypercholesterolemia, ALN-TTR01 for the treatment for ATTR and today ALN-TTR02 also for the treatment of ATTR. To date this positive clinical experience has employed three distinct delivery approaches, including inhalation of siRNA in a simple formulation, first generation LNP technology or SNALP from Tekmira and Alnylam’s proprietary second-generation formulation.

We will very soon add a fourth delivery technology to our clinical pipeline efforts with our GalNAc-siRNA conjugate approach that we are employing in our ALN-TTR subcu effort and with ALN-AT3, an exciting RNAi therapeutic program for the treatment of hemophilia where we reported some exciting news just this last week.

In aggregate, these data support what we have always believed. RNAi can be harnessed in man to create a whole new class of high impact, innovative medicines. Now as Akshay will detail for you in a moment, we presented result today demonstrating that administration of ALN-TTR02 leads to robust knockdown of serum TTR protein levels above the 94%. Knockdown of TTR was found to be rapid, dose- dependent, durable and specific after just a single dose.

Taking a step back, we believe this data with ALN-TTR02 established new industry milestones in our continued efforts to advance RNAi therapeutics divisions. These data are important for several reasons. First, they demonstrate the highly robust level of target gene knockdown, an attractive pharmacologic profile that is achievable with RNAi therapeutics. In fact, these results are certainly the most striking results ever reported for RNAi therapeutics in man and they highlight the potency of the RNAi pathway.

Second, these results demonstrate for the first time specificity for RNAi therapeutics in humans. Further, these results illustrate the very significant potency improvements that we've made with second generation LNPs and the critical importance of those improvements and the advancement of high-impact RNAi medicines to patients.

And finally, these results mark important progress in our overall Alnylam 5x15 product strategy efforts where we are advancing RNAi therapeutics with a focus on genetically-defined targets for diseases where there are limited treatment options for patients and their caregivers. Specifically, these results highlight the attractiveness of our strategy where we are focused on high unmet need settings with genetically-defined targets in the liver, where we get excellent delivery and with a Phase I biomarker that gives us great confidence as we advance toward Phase III and the market.

In our view this is a compelling strategy to build our company and also value for our shareholders. Of course there is much more do in our efforts to bring RNAi therapeutics to patients in need and everyone here in Alnylam is focused and passionate on making that happen. Indeed today’s results are a major step forward that further embolden us in our efforts.

Now before I turn the call over to Akshay, I want to invite each of you to an event that we are holding tonight at 5 PM this evening at the Palace Hotel in New York City where we will review these data in more detail and also discuss what they mean for Alnylam. Please look for the invite in your email or contact Cynthia Clayton for more information. So let me now turn the call over to Akshay. Akshay?

Akshay Vaishnaw

Thanks, John and hello everyone. This is indeed an exciting day for us at Alnylam and also for patients afflicted with ATTR. As most of you are aware, ATTR is a devastating, hereditary and often fatal disease caused by mutations in the TTR gene. As an orphan disease, ATTR afflicts proximately 50,000 people worldwide and is associated with significant morbidity and a mean life expectancy of between 5 to 15 years from symptom onset. Liver transplantation is the current standard of care and only a subset of patients is actually eligible for that invasive procedure. As a result there remains a significant need for novel therapeutics. Late last year, a new drug for the treatment of ATTR in FAP patients was approved in Europe called VYNDAQEL, otherwise known as tafamidis. However, just recently it was not approved by the US FDA. Importantly for us, tafamidis has paved a clear path for the future clinical development of therapeutics to treat ATTR.

It's very clear that new therapies are still needed for the treatment of ATTR and we believe that our mechanism for action namely silencing of the disease causing TTR gene leading to knockdown of the circulating TTR protein has the potential for generating a more profound therapeutic impact. It's important to note that ALN-TTR02 is designed to knock down both mutant and wild-type TTR since both are important in the pathogenesis of disease. The result as illustrated on slide eight is that unstable circulating TTR tetramers are reduced resulting in prevention and then clearance of amyloid deposition in tissues, which we believe will lead to stabilization and recovery from polyneuropathy and cardiomyopathy.

I would like to now turn to discussion of the preliminary ALN-TTR02 Phase 1 results. The Phase 1 trial was conducted in the UK as a randomized single-blind, placebo-controlled, single-ascending dose study. The study enrolled 17 healthy volunteers. The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. In addition, pharmacodynamic and clinical activity for ALN-TTR02 were measured based on circulating serum TTR protein levels through at least day 56 following a single dose.

Additional objectives included plasma and urine PK. As you can see from the table on slide 10, in this study ALN-TTR02 was found to be generally safe and well tolerated. There were no serious adverse events or discontinuations and there were no significant adverse events associated with ALN-TTR02 up through 0.3 mg/kg. A moderate acute infusion reaction was observed in one subject receiving ALN-TTR02 at 0.5 mg/kg, although the subject was able to complete dosing with a slowing of the infusion rate.

This infusion reaction seen with other lipid-based therapies was similar to those reported in our prior clinical trial experience with other LNP including ALN-VSP and ALN-TTR01. Importantly there were no laboratory abnormalities including no changes in liver function tests, cytokines or CRP. As John mentioned results from the study showed that a single dose of ALN-TTR02 resulted in rapid dose-dependent, durable and specific knockdown of serum TTR levels. The overall results were highly statistically significant with a P value of P less than 0.00001. Even at doses as low as 0.15 mg/kg substantial serum TTR suppression was achieved, where a mean 82% reduction was observed at nadir.

At the next cohort of 0.3 mg/kg, an 87% mean TTR knockdown was achieved at nadir, with a mean of 67% reduction still observed 28 days post dose. In the one subject treated at 0.5 mg/kg, a reduction of 94% was observed at nadir with 77% suppression maintained at day 28. When using the less sensitive but more commonly used turbidometric assay method, three of the four subjects at 0.3 mg/kg up or greater showed undetectable levels of TTR on one or more post dose samples. Based on this very substantial TTR knockdown observed at 0.15 and 0.3 mg/kg, dosing at the 0.5 mg/kg level was limited to one subject. Importantly ALN-TTR02 exhibited a rapid onset of action and a durable response. In fact over 50% knockdown in TTR was achieved by day three in all of the 0.15, 0.3 and 0.5 mg/kg subjects and nadir levels were achieved between days 10 and 14.

Regarding durability, a simple dose of ALN-TTR02 maintained substantial TTR knockdown for weeks and we believe that this pharmacodynamic profile supports at least Q4 weekly dosing and possibly even Q6 or Q8 weekly dosing going forward. We look forward to evaluating this in our Phase II study that has recently been initiated.

The key results are summarized here for you on slide 13 and there are also a number of additional findings that we presented today that you can see in our presentation materials posted on our Capella site. I want to highlight several important observations. First as expected TTR knockdown was found to be closely correlated with reductions in levels of retinal-binding protein and Vitamin A. Further we were very encouraged by the very low inter-subject variability as evidenced by the low standard deviation values at doses of 0.15 mg/kg and above, a rather low level of variance in any experiment of in vivo biology, let alone a human clinical study.

Also in a separate Phase I study using ALN-PCS, an RNAi therapeutic targeting PCSK9, we were able to measure serum TTR levels and show the absence of any serum TTR knockdown as one might expect. Since ALN-PCS uses the identical LNP as ALN-TTR02, this finding now confirms in vivo in humans, the specificity for RNAi therapeutics.

Finally, a rather striking result of the study was an analysis performed to look at the correspondence of TTR knockdown in humans as compared with non-human primates. Specifically, we observed essentially super-imposable curves for TTR knockdown at the same mg/kg dose. Certainly these preliminary results give us great confidence on the human translation of RNAi therapeutics based on non-human primate pre-clinical studies.

And so in summary ALN-TTR02 showed a favorable safety profile and very encouraging robust and durable knockdown of the TTR. These results document an unprecedented level of clinical activity for RNAi therapeutics and strongly support advancement of this innovative program to meet the needs of ATTR patients. Knockdown of circulating TTR is a validated endpoint in ATTR based on the data from patients receiving liver transplants.

Furthermore, evidence from other systemic amyloidotic diseases shows that as little as 50% reduction of the disease causing protein can result in disease improvement or stabilization and accordingly these data provide key human proof-of-concept with associated clinical relevance as we advance this medicine to patients for the treatment of ATTR, a devastating orphan genetic disease.

As most of you are aware, we recently initiated a Phase II study of multi-ascending doses of ALN-TTR02 in ATTR patients. We look forward to continuing to share clinical data from our exciting ALN-TTR02 program and assuming positive results in the Phase II study, our goal is to advance to a pivotal trial in 2013.

And with that, I will turn it over to the operator for your questions. Operator?

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) And your first question comes from the line of Charles Duncan with JMP Securities. Please proceed.

Charles Duncan - JMP Securities

My first question is, this is obviously a pretty big jump in the percentage knockdown relative to the first-generation technology. I am wondering if you can review for us what you think is the key attribute that could explain this.

John Maraganore

Yeah, Charles. I’d be happy to do that and Akshay can join me as well. Obviously, the key advance that was made with second-generation lipid nanoparticles was the discovery of novel lipids and quite by chance, just this past Friday, there was a paper published, that describes that discovery and I’d encourage you to read it because that paper really describes exactly the work that was done to generate these novel lipids that obviously are having just over the weekend we now can represent the human data, a very significant impact in human translation.

So, it’s very gratifying to see this scientific paper from our chemist on Friday now being presented in a human study with exactly to your point such profoundly improved in vivo potency in man with TTR02. So it really comes out on these novel lipids.

Charles Duncan - JMP Securities

And so, John, also, I guess my question is kind of along the lines of dose response but this increased knockdown should result in increased clinical benefit not only in terms of TTR reductions but also call it improvement from polyneuropathy. So how does this impact your views on subsequent clinical development and handicapping success?

John Maraganore

Yeah, let me turn that over to Akshay.

Akshay Vaishnaw

Well, Charles, we’re obviously very excited about these data. Obviously, we agree this is profound knockdown and it bodes well in terms of clinical translation, substantially reducing the pathogenic protein in systemic amyloidosis is what needs to be done. 50% of greater reduction has have in a profound impacts in AL amyloidosis, in AA amyloidosis and others. We are well north of that, so I think at this point in time its speculative but we are confident that we will see substantial clinical benefit and as you see at these top three doses we are well more than 80% knockdown and beyond that it's hard to predict that we are going to move aggressively forward, hopefully, with the Phase III program next year and that is what we reveal all in terms of translation of this kind of strong pharmacodynamic activity to benefit from patients with polyneuropathy and/or cardiomyopathy.

Charles Duncan - JMP Securities

And then my last question is if I recall which I may not completely recall the results from the TTR01, the first-generation technology it seems like you are getting pretty substantial or not nearly these levels of knockdown but you are getting pretty respectable knockdown levels and in fact levels which exceeded the 50% reduction that you estimate to be kind of a minimum level for clinical benefits, so I am kind of wondering why pursue this next-gen technology is it just to provide headroom for those kind of results?

John Maraganore

Well, Charles, the TTR01 data that we presented first of last November and then we recently showed a mean knockdown of 38%. So a clearly a even at 1 mg per kg so clearly we are seeing a 0.15 mg per kg we are seeing an 80% knockdown. So the level of knockdown with TTR02 is substantially better. We do see one patient with TTR01 that showed more robust roughly 80% knockdown but in that group in the one mg per kg group there was variation between subjects ranging from 25% knockdown to 80% knockdown. Obviously with TTR02, we are seeing you know essentially at 10th of the dose we are seeing far more significant knockdown that's consistent. So, I think the data are pretty clear that this is a go-forward go-to-market production.

Charles Duncan - JMP Securities

So if they jump in potency and much less variability?

John Maraganore

Absolutely.

Operator

Your next question comes from the line of Geoff Meacham with JPMorgan. Please proceed.

Geoff Meacham - JPMorgan

So, when you look at the median serum TTR in this study its about 290 maybe help us with how this would compare to ATTR patients and what if any changes you would make based on the data on your Phase II based on the data for today?

Akshay Vaishnaw

Yeah, Geoff so the median patient levels are little bit lower actually particularly the disease advances, but the more important point for us has been and you are asking important question both in this program and other programs like PCSK9 program for Hyperlipidemia. If you look at the starting levels of the target, we get equivalent knockdown regardless of the starting levels. So the levels are actually somewhat lower in the patients and the percentage of fact is regardless of the starting levels. So we are confident that with such effects at 0.15 and above we are going to get very good translation.

John Maraganore

And just one other point Geoff to follow-up and I would add to that if you may recall our TTR01 presentation in April, we showed using a proteomic analysis we showed some very nice correspondence of knockdown of wild type with mutant TTR essentially a one-to-one correspondence in that study. So we are pretty comfortable and confident about how that will translate with TTR02 in the current Phase II study.

Geoff Meacham - JPMorgan

Got you. And then so I guess the follow-up to that would be, you feel pretty comfortable and you don’t feel like you have to go to a higher dose at this point?

John Maraganore

No, not at all.

Geoff Meacham - JPMorgan

Okay. And then is this just a duration that you guys showed I guess on slide 10 and 11 that informs your thought that this could be Q4 weeks or Q8 weeks, what other things could play a role in the frequency and do you think that, that has any kind of looking down the road or any kind of real a commercial implication?

John Maraganore

Well, it’s let me answer it and then may be Barry and Akshay can comment as well. I think if you look at the curves on slide 11, you can see that let’s take the point three or point five. You can see that at one month you are still 60% to 80% knockdown and so then with the next dose if you do Q4 weekly, you are going to see that ratchet down to over 90% its certainly our estimate. And essentially overtime if you go Q4 weekly once monthly you are going to see that just clamp down of TTR levels which is a therapeutic objective in this approach. But one could imagine spreading that out more because as you clamp it down overtime either you could imagine the concept of Q6 weekly or Q8 weekly type dosing in the setting. We will have to explore that in our Phase II. But that is interesting because then the treatment of these patients might be a six time per year type visit to their physician and that has I mean 12 times a year is not bad by any stretch but six times a year is even a little more interesting. So we’re interested in exploring that. I would say we’re very confident with Q4 weekly. I think those are very clear in the data sense that you see here but as we do multi-dosing, we’re going to be interested in looking at other dose regimens as well. Barry, Akshay, anything want to add to that.

Akshay Vaishnaw

No, I mean not from a technical viewpoint I think you got it covered and certainly these data open up some very interesting vistas in terms of what might be possible. And that’s why you are opting to. So it’s going to be fun exploring that.

Operator

Your next question comes from the line of Marko Kozul with Leerink Swann. Please proceed.

Marko Kozul - Leerink Swann

I was wondering if you could give us your latest thoughts in terms of what you’re learning and applying to your TTR program on the clinical and regulatory fronts from the recent Pfizer tafamidis events as well as the ongoing Phase III NIH diflunisal program.

John Maraganore

Yeah, great question. Akshay, do you want to handle it?

Akshay Vaishnaw

Yeah, Marko, I mean, yes very important. What did we learn from the tafamidis experience at the US FDA? Clearly, this was an important effort and I think what was not in debate at the meeting, in fact there were elements of the data sets that were very supportive of clinical benefit to patients. The big learnings where that of panel in particular was very impressed by the fact that the drug acted directly on the pathogenic protein and there was a long discussion around, the potential of a biomarker based approval, as you may recall and exactly while the panel itself solved that the trend that we undoubtedly seen in some of the data suggest in clinical benefit was sufficient to warrant approval and the agency disagreed and the agency's argument was we found largely a technical argument based on the factor that this was a single study with most of the data being derived from one center and therefore the discrepancy that occurred between the intent-to-treat and the per-protocol analysis sort of marred by nullified some of the positive trends in the data.

And so the learnings for us well we are going to have a strong international multicenter asset, we are going to obviously balancing enrollment across science so we don’t get in a trap like that. We are going to obviously we've learnt a lot of actually about powering studies in TTR on the tafamidis experience and we are going to power in a way that accounts for potential dropouts and things like liver transplant as well as we are surely confident that we would hit both across ITT and EP and we have learnt a lot about the subtleties from some of the trends that we are seeing in tafamidis or what kind what aspects will polyneuropathy responsive to that drug, in what domains of the NIS-LL scoring system which is particularly helpful.

So you know we are going to [factor] all about in and as well as noting that you know and it was noted on the data that tafamidis was beginning to show clinical benefit in six months in terms of separation NIS-LL scores between tafamidis and placebo and that increase widened in 12 months and that was 18 months and with the kind of substantial impact we have are seen in today’s dataset, it gets us excited about thinking all about how long our trial has to been 18 months of the tafamidis study perhaps not you know given out significant impact on the pathogenic protein and even with tafamidis. We still remove the protein that we are seeing in clinical benefits beginning at six months so these are the learnings and you know we obviously look forward next year when we want to get into Phase III sharing with you guys how close folks have been integrated into the ultimate design.

Marko Kozul - Leerink Swann

Akshay thanks for that answer, you know I just wanted to follow-up and ask if you had any thoughts on size of the study and did you mention potential for 12 month endpoint or 18?

Akshay Vaishnaw

Well, what I said was about the tafamidis so it was an 18 month endpoint but given that even with that drug at relative modest potency from our perspective, they were beginning to see benefit of six months. With that rate of potency against the pathogenic protein we feel that something shorter than 18 months might be feasible you know in terms of the length of our primary endpoint again to slightly to speculate on the exact timeframe but we are just alluding to that and yeah sorry, what was your other question Marko?

Marko Kozul - Leerink Swann

Possibly the size, the sample size.

Akshay Vaishnaw

Yeah, I mean again let's finish our diligence here and then talk with you in a very informed way but note that the tafamidis study was just shy of a 120 patients and they just missed the ITT because of dropouts, because of liver transplantation and again with a relatively modest clinical effects so and if we are hypothesizing at least that degree of clinical effect or data then I don't see our study being hundreds and hundreds and hundreds of patients. It would be in a similar ballpark but the diligence is on going right now.

Marko Kozul - Leerink Swann

Thank you for those answers and just one quick broad question, I didn't quite catch what you had mentioned about the correlation between the non-human primate data and human data and what the…

John Maraganore

Yeah, if you look at the data that's on our website there's an analysis that looks at the knockdown of TTR in our human study here at 0.3 mg/kg in comparison to a dose that we just happen to have the dose in non human primates at 0.3 mg/kg and the curves are virtually super imposable. I mean it's almost beyond expectations of anything in vivo biology to see that type of correspondence let alone relationship between a human clinical study result with an a non-human primate result. Its striking I think you should take a look at it.

Marko Kozul - Leerink Swann

And John what's the predictive value of that for some of, for this vehicle for some of your other programs, thanks.

John Maraganore

Well, you know every time we look at non-human primate data now we sort of think that that's going to be pretty consistent with what we see in humans and that's an amazingly powerful predictive value.

Operator

Your next question comes from the line of Mike King of Rodman & Renshaw. Please proceed.

Mike King - Rodman &Renshaw

Maybe a lot of my basic questions have been answered but maybe one more forward a little bit. I see by clinicaltrials.gov, it says your Phase II was updated on June 11, so have you actually started to treat patients yet or are you still waiting to tweak the protocol as per your thoughts on the dosing intervals.

John Maraganore

No. The study was initiated Mike. So when we initiated the study that means that we treated the patient.

Mike King - Rodman &Renshaw

Okay, so can you, it sounds like you are still thinking about different durations and how should we think about, how you guys are going to implement that.

John Maraganore

Well, right now the protocol is aimed at Q4 weekly dosing, okay. But what may you know when we will continue it down that path but as the study progresses you know there's always opportunities to look at and consider amendments in terms of the dose intervals.

Michael King - Rodman & Renshaw

So, and it seems that there are about 28 patients are expected to enroll that might you increase that size or just treat some remainder patients at different intervals?

John Maraganore

There is no reason to think that we should do that, at this point in time, we always have obviously if we choose to do it in the future we can always amend the protocol, but that’s something which is not in our plans nor to increase the size.

Michael King - Rodman & Renshaw

Let me ask a quick tolerability question if I may. The erythema, no patient dropped out for that, clearly, but I am just wondering in terms of long term therapy what the implications are here and where there any premeds used or might you envision premeds being used to reduce the incidence?

Michael King - Rodman & Renshaw

Yeah, Akshay you want to handle it?

Akshay Vaishnaw

Yeah, sorry Mike you kind of dropped off at the end, and reduce the incidence all……

Michael King - Rodman & Renshaw

Of erythema; say you’ve got two out of three at 0.3 and then the one patient at 0.5 in erythema, so what can we do to manage that better?

Akshay Vaishnaw

Yeah so erythema of course means redness of the skin; it’s very mild, it’s very transient. I think the subjects didn’t notice it themselves generally speaking these kind of things are picked up by the investigators. They have to scrutinize them very carefully. Didn't bother them at all and was gone within 24 hours. All the subjects both on placebo and on our TTR02 received the premed (inaudible) of steroid and both the interpretation of the investigators of this site embedded the steroid in the premed that gives this slight flushing or redness and that’s why it’s transient and non-bothersome and we don’t really see that as an issue moving forward.

Michael King - Rodman & Renshaw

Okay, alright. And then I guess this obviously what happens when we go to multiple doses whether that tamps down or not; would it have any implications do you think for GalNAc for sort of injection site reactions or is it just too early to tell?

Akshay Vaishnaw

Well again, you see in the placebo subject here as well. So it’s associated almost certainly with the steroids. Steroids do cause flushing or redness, that’s known. And so we don’t see how that is bearing on the GalNAc, obviously the safety on that program we’ll learn about in due course; but no, we are not at all concerned about the GalNAc sub-conjugate efforts based on this observation.

John Maraganore

Yeah, but just add that, you know, obviously one of the advantages of the GalNAc approach is it’s not a lipid-based approach and so we’re not expecting to do any premed with the GalNAc approach.

Michael King - Rodman & Renshaw

And then one final one if I may; I mean, did you guys look at, you didn’t look at messenger RNA for TTR?

John Maraganore

You know, it’s a great question. Mike obviously, we didn’t do any liver biopsies in the study, but as you may have seen earlier in the year, we presented some data around capturing mRNA’s from exosomes of animals, circulating messenger RNA and there are some ongoing work and we will inform about that when we can, but certainly the protein level is quite clear in this case.

Operator

Your next question comes from the line of Alan Carr with Needham & Company. Please proceed.

Alan Carr - Needham & Company

Following on to Mike’s question a little bit. In terms of infusion reaction, it sounds like that something that, I mean, you have seen that at higher doses before and you saw at 0.5 here. I am wondering how much you had to slow it here as an addition to previous extensions to the period of infusion or not. I guess the straight forward question is how long does it take to infuse?

John Maraganore

Yeah, so all the subjects receive drug over a one-hour interval. This particular subject was just after that one-hour period. The drug was being administered, that was mild to moderate infusion reaction that stopped and within 15 minutes or so it was re-initiated. And I believe the entire infusion was then completed in over two hours instead of the schedule of one hour, which was then completed uneventfully and everything is fine.

Alan Carr - Needham & Company

And then for this upcoming trial, I am wondering if you guys can give us any more details about it. I don’t think you’ve disclosed the doses and it sounds like you may, I am wondering if you can disclose those? And then also it sounds like you may take the opportunity to try every four weeks as the protocol says, but also every six and every eight weeks?

Akshay Vaishnaw

You know, we haven’t disclosed doses, but you can anticipate that we will be evaluating a spectrum of doses that encompass the work you’ve seen today. And as John was mentioning, the initial intend is to demonstrate the two, four weekly dosing as associated with significant knockdown and given the excitement around today’s data, there will always be opportunities either through an amendment or other mechanisms to look at potentially six-weekly or eight-weekly down the line, but the intend right now is what's going on as the Q4 week emerge.

Alan Carr - Needham & Company

And when in 2013 can we expect results from this Phase II TTR02? Have you narrowed down beyond to within 2013 or just…?

John Maraganore

We haven’t yet, Alan and we will, you know, we’re just – that study just started last month. So obviously we want to have a sort of level of grow behind us before we can give you a real assess of what the timing is so you know bear with us until the fall herein we’ll probably provide some more guidance at that point.

Alan Carr - Needham & Company

And then I have kind of a big picture question. You have a lot of human experience now I am curious how your interaction with the FDA or I guess the FDA’s response to RNAi or sentiment around RNAi has evolved this as well accumulated patient data here especially with respect to safety and building that sort of thing?

John Maraganore

Yeah, it’s a great question; Akshay you want to handle it?

Akshay Vaishnaw

Alan, we have had very good receptions for outlook for a long time now. We have been invited on two occasions to give CDER wide seminars on the status of RNAi discovery and development. Last one was just a few years back now before this data came in. We need at least annually at international meetings with the meeting that turns in DC typically once every year convened by the DIA and all it goes where all the regulators pretty much show up and not just from the US, but also significant numbers from Europe and Canada.

And at the in last meeting in spring we discussed the TTR01 data, the PCS data, the liver counts data very well received. And you know I think the data today just highlighting further, the potential for benefit and as you have said we had a significant clinical experience and so far the safety profile has been encouraging. So that package has been received well and we are really looking forward now to engaging regulators globally, not just here around the design for our pivotal study for TTR02 which we want to kick off next year and in our anticipation that should be a good meeting.

Alan Carr - Needham & Company

Will you start those meetings after you have, I mean is that something that could start this year or do you want to wait till after this Phase II TTR02 trials are wrapped up?

Akshay Vaishnaw

Yeah Alan, our regulatory strategy we generally don’t sort of get into that but, I think what hopefully is important to everybody is that we design a protocol that's widely accepted and found to be supportive of the endpoint we want to demonstrate and as soon as we have a confirmation of that and the design of that and a consensus around that we would investigate some regulators; we’ll be sure to share it with the group.

John Maraganore

Just to be clear Alan we are not saying that we would pursue a SPA in this protocol; I want to make sure that that's clear.

Operator

Your next question comes from the line of Megan Mccloskey with MLV & Company [McNicoll Lewis & Vlak LLC]. Please proceed.

Megan Mccloskey - McNicoll Lewis & Vlak LLC

Congratulations on the great results; its very encouraging to see such great data after the single dose. We were curious about what you might be expecting looking forward when taking the implication for multiple doses, are there any specific AE’s you are concerned about becoming unmasked on the mutation background with multiple doses? And we are also curious about whether or not you will be looking at paying or some of the neuropathy issues in the Phase II moving forward and what you expect to be able to see from a specific level of knockdown as far as clinical benefits?

John Maraganore

That's a great question Megan. Akshay?

Akshay Vaishnaw

Yeah, from adverse events, we don't really see things changing substantially based on transitioning from this healthy volunteer study into patients setting and such. We have very substantial patient based experience in our LNP programs; most importantly from our liver counts program. And there beyond the adverse events you would have seen end stage cancer patients really from the LNP viewpoint we weren’t really seeing anything dramatic or significant. So no I mean at this point in time we are very optimistic about the adverse event profile. Yes we have seen this in infusion reaction; one subject where they maybe a low level incidence of infusion reactions, but again, it was just one subject out of the whole group, yeah so that’s great.

Beyond that, just can’t really speculate much more on that and in terms of what do we expect to see in terms of activity, currently the study is designed as a two cycle as in two doses separated by four weeks and so really expecting to see much from the viewpoint of polyneuropathy over two month interval; unlikely, I would say, obviously we are going to be monitoring the pharmacodynamics in great detail to confirm the dosing regimen we want to carry forward. In all likelihood to see the translation of these wonderful PD’s that pharmacodynamic effects, clinical activity will require longer than two months dosing.

Operator

Your next question comes from the line of Stephen Willey with Stifel Nicolaus. Please proceed.

Stephen Willey - Stifel Nicolaus

I was just wondering if you guys have and I don’t think that you presented that yet but have you teased out the percentage knockdown of wild type versus mutant TTR in the TTR01 study and I guess there is not a reason to think that there would be a difference in affinity between the two at all?

John Maraganore

Yeah Stephen if you go the presentation that we showed in April at the International Symposium of Amyloidosis, which is on our Capella site, you will see a very -- we’ve developed an assay using mass specs that allows us to measure the levels of the specific mutant protein in the circulation and what you see in that study, result in that presentation was a very nice correspondence of knockdown between wild type and mutant protein, one-to-one.

And so, you know, we feel pretty confident that then that result for TTR01 will of course translate with TTR02 because the siRNA is identical between the two of them. And so I think that answers your question very specifically. We’re still developing the same aspect assay for other mutants, but that data point alone obviously clearly shows that we’re getting knockdown other mutant protein and the wild type protein in humans.

Stephen Willey - Stifel Nicolaus

And then I know that you’ve talked recently about moving GalNAc conjugated subcu for TTR into the clinic perhaps sometime early next year. I know, John, you talked about this potentially being a six-times per year dosing regimen so I guess, how do you – do these results change your thinking along that front?

John Maraganore

You know, I think that we’ve always do the TTR subcu program as part of how we think of broadening out the opportunity. I mean, TTR amyloidosis is not just FAP and is not even just symptomatic with FAP carriers; it’s the cardiomyopathy patients and it’s also the senile form of the disease, systemic amyloidosis which is wild type protein.

So we view the subcu opportunity as an opportunity for broadening out our overall therapeutic opportunity and commercial opportunity for the study. Obviously, TTR02 we’re going to progress to the market until pivotal and we will learn through the next year what the dose treatments it will be in the pivotal study; when we set that dose frequency and conservatively you know it’s probably going to be Q4 weekly, but it could have upside into broader less frequent dosing but we will know that by sort of middle of next year and that is going to be clear to everybody but it’s going to be data driven Stephen and we’ll use the data to inform our decision on that. The subcu program is more likely going to be once weekly time subcu dosing.

Operator

And this concludes the question-and-answer session for today’s call. I would now like to turn the call back over to the company for any closing remarks.

John Maraganore

Great thanks and thanks everyone for joining the call this morning for what we believe is a very important set of clinical results for RNAi therapeutics. Again, I want to extend the invitation to our venture tonight at the Palace Hotel for a deeper dive on data and I hope to see all of you there. Thanks very much.

Operator

Ladies and gentlemen that concludes today’s conference. Thank you for your participation. You may now disconnect. Have a great day.

Copyright policy: All transcripts on this site are the copyright of Seeking Alpha. However, we view them as an important resource for bloggers and journalists, and are excited to contribute to the democratization of financial information on the Internet. (Until now investors have had to pay thousands of dollars in subscription fees for transcripts.) So our reproduction policy is as follows: You may quote up to 400 words of any transcript on the condition that you attribute the transcript to Seeking Alpha and either link to the original transcript or to www.SeekingAlpha.com. All other use is prohibited.

THE INFORMATION CONTAINED HERE IS A TEXTUAL REPRESENTATION OF THE APPLICABLE COMPANY'S CONFERENCE CALL, CONFERENCE PRESENTATION OR OTHER AUDIO PRESENTATION, AND WHILE EFFORTS ARE MADE TO PROVIDE AN ACCURATE TRANSCRIPTION, THERE MAY BE MATERIAL ERRORS, OMISSIONS, OR INACCURACIES IN THE REPORTING OF THE SUBSTANCE OF THE AUDIO PRESENTATIONS. IN NO WAY DOES SEEKING ALPHA ASSUME ANY RESPONSIBILITY FOR ANY INVESTMENT OR OTHER DECISIONS MADE BASED UPON THE INFORMATION PROVIDED ON THIS WEB SITE OR IN ANY TRANSCRIPT. USERS ARE ADVISED TO REVIEW THE APPLICABLE COMPANY'S AUDIO PRESENTATION ITSELF AND THE APPLICABLE COMPANY'S SEC FILINGS BEFORE MAKING ANY INVESTMENT OR OTHER DECISIONS.

If you have any additional questions about our online transcripts, please contact us at: transcripts@seekingalpha.com. Thank you!

Source: Alnylam Pharmaceuticals' CEO Discusses the clinical results from its ALN-TTR02 Phase I clinical trial (Transcript)
This Transcript
All Transcripts