Alnylam Pharmaceuticals' CEO Discusses ALN-TTRsc Phase I Clinical Data (Transcript)

Executives

Cynthia Clayton - Vice President, Investor Relations and Corporate Communications

John Maraganore - Chief Executive Officer and Director

Barry Greene - President and Chief Operating Officer

Akshay Vaishnaw - Senior Vice President and Chief Medical Officer

Analysts

Geoff Meacham - JPMorgan

Alethia Young - Deutsche Bank

Marko Kozul - Leerink Swann

Alan Carr - Needham & Company

Ted Tenthoff - Piper Jaffray

Stephen Willey - Stifel

Alnylam Pharmaceuticals, Inc. (ALNY) ALN-TTRsc Phase I Clinical Data Conference Call September 23, 2013 8:00 AM ET

Operator

Welcome to the Alnylam Pharmaceuticals conference call to discuss interim clinical results from their ALN-TTRsc Phase I trial. (Operator Instructions) I would now like to turn the call over to the company.

Cynthia Clayton

Good morning, everyone. I am Cynthia Clayton, Vice President of Investor Relations and Corporate Communications at Alnylam. On the call with me today are John Maraganore, our Chief Executive Officer; Barry Greene, President and Chief Operating Officer; and Akshay Vaishnaw, Executive Vice President and Chief Medical 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 Investors page of our website, www.alnylam.com.

During today's call, as outlined on Slide 2, John will provide some context on our ALN-TTRsc clinical results and what they mean for the program Alnylam and for the RNAi field. Akshay, who is on the call remotely, will then review the results of the ALN-TTRsc clinical study. Barry will review our upcoming milestones, and we will then turn the call over to you for your questions.

Before we begin, and as you can see on Slide 3, I'd like to remind you that this call will contain remarks containing 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 date. We specifically disclaim any obligations to update such statements.

I will now turn the call over to John.

John Maraganore

Thanks, Cynthia. Welcome, everyone, and thanks for joining us this morning. As you can imagine, we are very excited to share with you these positive clinical data from our ALN-TTR subcu Phase I study.

These human data are the first to be presented for our proprietary GalNAc-siRNA conjugate delivery platform, which enables subcutaneous dosing of RNAi therapeutics with a wide therapeutic index. These new clinical results clearly establish human translation for RNAi therapeutics that utilizes delivery platform.

Moreover, we believe these new results demonstrate an unmatched level of efficacy for RNA therapeutics with a consistent approximately 90% target gene knockdown via subcu dose administration, in addition to a very promising safety profile. More specifically to our TTR amyloidosis program, we believe these results establish a new benchmark for consistent and sustained TTR knockdown of approximately 90% for RNA therapeutics in development for ATTR.

Because of results like these, our GalNAc-siRNA conjugate delivery platform has now become our primary approach for execution on our Alnylam 5x15 product strategy and in addition to our TTR cardiomyopathy program, it is the platform we're using in our programs in hemophilia, porphyria, complement-mediated diseases, hypercholesterolemia, beta-thalassemia and alpha-1-antitrypsin deficiency, amongst others programs that are yet to be disclosed.

As a result, these data are very meaningful, not only for the continued advancement of ALN-TTRsc, but also for the continued execution on our entire Alnylam 5x15 product strategy. Through this strategy, we believe that we are building a compelling opportunity for shareholder value creation with a modular and reproducible approach for development and ultimately commercialization of innovative medicines for genetically defined disease.

We are in the midst of very exciting times at Alnylam with a steady flow of free clinical and clinical data. And these new results reflect the strong potential of RNAi therapeutics to become a whole new class of innovative medicines.

I'll now turn the call over to Akshay, for a more detailed review of the data. Akshay?

Akshay Vaishnaw

Thanks, John. As you just heard, these new ALN-TTRsc results represent a major milestone in our ATTR program as well as our entire pipeline of RNAi therapeutics. We believe this level of consistent TTR knockdown is exceptional and unmatched. And we now aim to advance ALN-TTRsc in future clinical studies with the goal of achieving approximately 90% TTR knockdown to maximize clinical efficacy.

As most of you are aware, our ATTR program is our lead 5x15 program. ATTR is a devastating, often fatal, hereditary orphan disease caused by mutations in TTR gene afflicting approximately 50,000 people worldwide.

There are two clinical presentations of ATTR. These include familial amyloidotic polyneuropathy or FAP, which affects approximately 10,000 people globally; and familial amyloidotic cardiomyopathy or FAC, which affects at least 40,000 people worldwide. Of course many patients also show evidence of mixed nerve and heart involvement.

New therapies are clearly needed for the treatment of ATTR, and we believe that our mechanism of action, silencing of the disease causing TTR gene leading to knockdown of the circulating pathogenic TTR protein has the potential to generate a profound therapeutic impact.

Now let me walk you through our ALN-TTRsc Phase I study and the results we have generated to date. As you can see over Slide 10, the Phase I trial is being conducted in the U.K. as a randomized, double-blind, placebo-controlled, single and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc.

Secondary objective include assessment of clinical activity of the drug as measured by serum TTR levels. In an initial single-ascending dose phase of the study, subjects receive subcutaneous doses of placebo or ALN-TTRsc from 1.25 mg to 10 mg/kg. In the multiple-ascending dose phase of the study, subjects receive 10 subcutaneous doses of placebo or ALN-TTRsc from 2.5 mg to 10 mg/kg.

As you can see on the Slide 11, interim data from the 28 subjects enrolled and analyzed in this study to date, showed that single and multiple dose administration of ALN-TTRsc resulted in rapid, dose-dependent, consistent and durable knockdown of serum TTR levels.

In the multi-dose cohorts, there was a statistically significant knockdown of serum TTR at all doses tested as compared to placebo. At a dose of 5 mg/kg, ALN-TTRsc administration resulted in up to 93.3% knockdown of serum TTR and a mean TTR knockdown of 87.5% at nadir. At a dose of 10 mg/kg, ALN-TTRsc led to up to 94% knockdown of serum TTR and a mean TTR knockdown of 92.4% at nadir.

By all accounts, this is an exceptional and unmatched level of TTR knockdown. Notably, during the period of dose administration, TTR levels are essentially clamped down showing a very consistent effect during dosing. In addition, we are very pleased to see a very rapid onset of action, with nadir achieved at about day 50, and then a very durable effect after cessation of drug with recovery to baseline levels at several weeks after.

And on the inside of Slide 11, analysis of TTR knockdown in humans as compared to non-human primates shows there's a highly correlated effect between the two species on a milligram per kilogram basis. Importantly, as John said, we believe these results unambiguously confirm human translation for our GalNAc-siRNA conjugate platform.

Now, our Phase I study is ongoing and we're currently enrolling subjects in additional cohorts to explore the activity of ALN-TTRsc administered weekly at a dose of 7.5 mg/kg as well as administration of ALN-TTRsc on once every two week dosing schedule. We'll use these additional data to finalize our dose and dose regimen selection for the start of our Phase II later this year with the start of our Phase III plan for next year, but we expect to be proceeding with either a 5 mg/kg or 7.5 mg/kg weekly or once a week two-week dosing regimen.

Setting up safety in this study, as reported to date, single and multiple doses of ALN-TTRsc were found to be generally safe and well tolerated. There were no significant or serious adverse events associated with the drug at doses through 10 mg/kg.

As detailed on Slide 12, all adverse events would be mild or moderate in severity. Injection site reactions were observed in the minority of subjects, including those receiving placebo. These are reported as being clinically mild and consist of transient erythema associated in minority of cases with edema or pain.

In all cases, these reactions were self-limiting and results completely typically within two hours of onset. Importantly there were no study discontinuations, flu-like symptoms or changes in cytokine, CRP, liver function test or kidney function or hematologic parameters.

In aggregate, these new data support our conviction that ALN-TTR has the potential to be an important therapeutic for the treatment of familial amyloidotic cardiomyopathy, a disease for which there are no approved therapies. Clearly, the ability of RNAi therapeutic to achieve a consistent approximately 90% knockdown of serum TTR sets a new benchmark that I believe has the potential to translate into meaningful clinical benefit for patients.

With these results in hand, we are well-positioned for continued execution on this program, which includes the initiation of a pilot Phase II study in FAC patients by the end of this year, and assuming positive results start of a pivotal Phase III trial with ALN-TTRsc by the end of 2014.

And with that, I'd like to turn the call over to Barry. Barry?

Barry Greene

Thanks, Akshay, and good morning, everyone. As you've heard we are demonstrating with robust human clinical data that the RNAi pathway can be harnessed to create high-impact innovative medicines. These new data point out our GalNAc-siRNA conjugate delivery platform as our primary approach for execution on our Alnylam 5x15 product strategy.

As a result, these data are very meaningful, not only for the continued advancement for ALN-TTRsc, but also for the continued execution of our entire Alnylam 5x15 product strategy. And while we have made tremendous progress since the start of the year, we still have some very exciting preclinical and clinical data presentations and milestones coming out of the rest to the year, as you can see on Slide 16.

As Akshay mentioned, we remain on track to start a Phase II study with ALN-TTRsc in cardiomyopathy patients later this year and are planning to start a Phase III trial in 2014. Now, with regard to our TTR02 program, we expect to present further data from our Phase II trial at the International Symposium on FAP in Brazil in November. These data will include full TTR knockdown data for about 30 ATTR patients.

For patients enrolled in Phase II study, we aim to begin an open-label extension study as well in the coming weeks. This study will include clinical data that will begin to readout in 2014.

Finally, we plan to initiative a Phase III pivotal trial for ALN-TTR02 in polyneuropathy patients by the end of the year. Without a doubt, this continues an exciting transition for Alnylam, as we enter advanced stages of our clinical development with our lead program.

Now, turning to our ALN-AT3 program for hemophilia, we've also made tremendous progress and are on track to file an IND for this program in the fourth quarter of this year and a Phase I start in early 2014. With our ALN-AS1 porphyria program we expect to identify a final development candidate for the program by late 2013 and to advance into clinic in 2014.

We also plan to nominate a development candidate for our ALN-CC5 program for complement-mediated diseases by the end of this year. For ALN-CC5, we'll provide clinical timeline guidance at the beginning of next year, but you can expect us to move this program forward quickly. And we plan to end the year with greater than $320 million cash.

Finally, with a number of scientific meetings from now to the end of the year, where our scientists will be presenting new data from essentially all of our 5x15 programs. In summary, I think it's clear that we are executing on our goal of advancing RNAi therapeutics with a potential to become an entirely new class of innovative, high-impact medicines for patients in need.

With that, I'd like to turn the call back over to the operator for your questions. Ellie, we'll take questions now.

Question-and-Answer Session

Operator

(Operator Instructions) Our first question comes from Geoff Meacham of JPMorgan.

Geoff Meacham - JPMorgan

I had a few questions. I knew you guys hadn't reported ISRs with the IV formulation, at least I don't remember that, but you have that here. Do you think that for subcu, this is the administration itself or is it some mechanism for the GalNAc delivery or is this problematic at all when you guys look at taking subcu into Phase III down the road? And I have one follow-up.

John Maraganore

Geoff, as you know, just about every subcutaneously-delivered drug has injection site reactions as a reported AE that true with HUMIRA, it's true with insulin, it's true with low-molecular-weight heparin. So it is very much a common phenomenon with subcutaneously-delivered drugs.

With an intravenous infusion of course, there you don't typically have these type of reactions, because you go to a hospital, you get an intravenous catheter administered. So it's a very different type of procedure. None of these injections site reactions that we're seeing are in any way, shape or form limiting, in terms of how we think about that. And the drug will be forward. Akshay, do you want to comment any further on that.

Akshay Vaishnaw

Yes, and I think couple of things over that is that as we described these reactions are very transient, lasting a couple of hours and this consist generally of redness. And importantly no one discontinued, no one was bothered by them, no. Action needed to be taken. And so they are very much, as John is saying, in keeping with other subcu drugs, which have been very successful. And in an indication like this we see nothing but green lights with these great data that we have to knockdown up to almost 94%.

Geoff Meacham - JPMorgan

And then the follow-up is for ATCR. From you guys, epidemiology work, are the mutations at the, let's say the less or more severe spectrum of disease that you can use to inform the entry criteria, when you guys look to start your pivotal later on this year?

John Maraganore

Yes, that's a great question. Akshay, do you want to handle that?

Akshay Vaishnaw

Geoff, just repeat that. I didn't quite get the angle on your question. Are the mutations less or more severe?

Geoff Meacham - JPMorgan

At the spectrum that you can somehow narrow the population or inform your entry criteria for the pivotal study.

Akshay Vaishnaw

I mean the genotype/phenotype relationships are pretty well understood, Geoff. And so we are fortunate to have a loss of literature and through our network of KOLs that we work within the FAC space. The kind of lion's share of FAC in the U.S. is taken out by this mutation V122I, which is dominant in the African-American population. And then there is T60A, and then there are about four others that are associated with FAC. So there's about half-a-dozen mutations that are well described, and we'll inform the design of our Phase III study.

John Maraganore

And Geoff, I'll just add, that in the Phase II that we're about to start, we'll look at a range of different genotypes in that study. It's not going to be restricted to any given genotype. So that will give us some experience across different genotypes prior to starting Phase III.

Operator

Our next question comes from Alethia Young of Deutsche Bank.

Alethia Young - Deutsche Bank

Just a question on like, in the open-label extension study, are you guys planning on communicating like different points with FDA about your progress there or is there any opportunity for breakthrough or faster pathway to approval?

John Maraganore

Alethia, that's a great question. We'll obviously keep the close touch with the FDA if there are compelling clinical data, we certainly will consider it. We'll go to the FDA and talking about our breakthrough, but we have to see how the data merge. Clearly that study is going to start very soon. There will be clinical endpoint data that we read out.

Theoretically, we'll going to give you some more guidance on that when we start that study. But there will be frequent, let me not use the word frequent, there will be periodic reviews of data that come out of that and obviously that's going to help our overall accrual efforts. In our TTR02 Phase III effort, it will obviously been meaningful for physicians to also see how that's progressing. And we'll certainly look at those data in the context of our interactions with the FDA. Akshay, anything you do you want to add to that.

Akshay Vaishnaw

No, no, I think that's exactly right. That's exactly right. We are excited to get the study going and we start to getting paid.

Alethia Young - Deutsche Bank

I hope you don't mind, just one follow-up. The three doses for the next three cohorts, can you just tell me what they are again, please?

John Maraganore

You mean the additional cohorts in the phase, the current Phase I.

Alethia Young - Deutsche Bank

Yes.

John Maraganore

So we are looking at a couple of things really. One, is we wanted to explore 7.5 mg/kg dose in that which is intermediate between the 5 and 10. And anything that we want to explore is in every other week dosing regimens. If you look at our data in our presentation from the multi-dose kinetics, you will see that the levels are very suppressed, and they seem after dosing has stop to be quite durable and it does open up the question of whether or not we can also explore once every two week dosing subcutaneously with our drug.

So we want to explore that in these additional cohorts. And I believe the additional cohort that's there is just a bulk of numbers in the overall population, so it's sort of in the same context of what's right there. Akshay, anything to add to that.

Akshay Vaishnaw

No, no, I think that's right. These initial interim data given there is a lot of guidance on different doses of regimen we'll explore. And I think it will be exciting to do that over the next couple of months.

Operator

Our next question comes from Marko Kozul of Leerink Swann.

Marko Kozul - Leerink Swann

I'd also like to echo my congratulations on your continued progress. My first question has to do with efficacy of GalNAc as a delivery platform. Can you give us a preview of where you might be headed in terms of further improvements and refinements? I think in this current Phase I TTR subcu multi-dose experience, you dosed up to 10 mg/kg.

And back in 2012 at OTS and on Slide 5, I think of your presentation this morning you appear to be achieving meaningful knockdown in the 2 to 3 mg/kg range for AT3 and PCS in pre-clinical models. So can you give us a preview of further improvements on where you might be headed?

John Maraganore

Yes. Thanks, Marko, that's a great question. The ALN-TTR subcu is the first GalNAc conjugate that we took into development. And obviously, we've now seen some very exciting and impressive results. But as all things in science, with a vibrant research group like we have here, there are constant improvements that we're making in these platforms and if that -- the benefit of that has been accrued in programs like our PCSK-9 program and our AT3 program as highlighted on Slide 5 of the conference call deck.

And you can clearly see that we're achieving ED80 type knockdown at doses around 1 milligram per kilogram. So it's about a tenfold, almost a tenfold, maybe a little bit less than a tenfold improvement compared to ALN-TTRsc. So we expect with AT3, which is about to start our clinical testing. We expect to be seeing 80% knockdown levels and doses that are in the 0.5 to 0.75 mg/kg level, which is really quite impressive. And we would expect to see similar type of effects with other GalNAc conjugates in the future.

So just exciting progress in general, and obviously the other thing, Marko, I will say is when we look at non-human primate data now with our GalNAc conjugates like we presented ISTH for our antithrombin program. We now know that that's one-to-one correlation in humans, based on the data you've seen today. So it's very exciting to able to have the confidence around that translation. And we just expect that to continue.

Marko Kozul - Leerink Swann

And just a quick second question that has to do with safety, which appears pretty clean in the poster and slides this morning. When you have final results from this Phase I study, what additional safety info will we have?

John Maraganore

Marko, we'll just have additional patients to look at and obviously look at that in the totality of the existing data sets. But I think also we'll soon be patients with this drug. And we'll soon be generating additional data, both efficacy and safety in patient populations and you will be seeing some of those data next year.

Operator

Our next question comes from Alan Carr of Needham & Company.

Alan Carr - Needham & Company

One of them, can you give us an update on -- any update on regulatory discussions around the upcoming Phase III trial? And then also, I guess a bigger picture question around the safety database here, how many patients have you been in with IV and subcutaneous across each of these some different platforms? And then the third one to follow-up on a previous question, it looks like you're doing, if you got three more cohorts, is it 7.5 every week? And then the other two are 5 and 7.5 every other week?

John Maraganore

Let me answer the first one or the last one first, which is its 7.5 mg/kg in two cohorts weekly and then there is an additional cohort of 7.5 mg/kg every other week, is the current lineup of what we're doing into Phase I. And again those data, we'll likely present those data or report on those data some time next year.

But as it relates to the first question on the regulatory discussions for TTR02, I can tell you that they are extremely well. We're pleased with the feedback we've gotten thus far. We don't foresee any issue from where we stand today, in terms of how we will proceed with the protocol and stay tuned on final details of the design, when we're going to report on them. But I think that we're quite pleased with those discussions. Akshay, anything to add on that point.

Akshay Vaishnaw

No, I think that's exactly right.

John Maraganore

And then you're challenging me now on the second question to sort of actuarially come together with numbers for you. So let me give you top-of-mind numbers. Our TTRO2 Phase I study was around 19 patients as I recall the number and our TTRO2 Phase II study that's going to be presented -- the final results will be presented in November, is about 30 patients. Our TTR subcu Phase I study that we presented today is 28 subjects. And obviously by the end of the additional cohorts it will be an additional -- Akshay help me out here.

Akshay Vaishnaw

No, I was just going to jump in, John. When we did R&D Day in July and added up the numbers, then at that point we had about 175 patients and the subject exposed in a various systemic deliveries human studies that we've done, so from our liver cancer program, TTRO1, TTRO2, PCS and others. And so John was giving you individual numbers from some of those studies, but at that number will soon to approach to 100.

We've given over 500 doses of intravenous Lipid nanoparticle based drug over two years of dosing. And in this current TTRsc study we'll of course top-out at around 40 individual exposed. So we're getting to a significant database and as we progressively shared the safety and efficacy information, obviously we're excited about the profile emerging for our drugs, both IV and LMP from a safety and efficacy viewpoint.

Operator

Our next question comes from Ted Tenthoff of Piper Jaffray

Ted Tenthoff - Piper Jaffray

So I guess my question sort of gets back to sort of a higher level, and I love the fact that you have the optionality around the IV and subcu and are now entering into FAC as well. But maybe tell us a little bit about how you see the future treatment of FAP. And obviously this is going to be data-driven, but is this a disease where maybe less-severe patients will be treated with subcu or maybe patients will be on-boarded first with IV to get disease under control? With this really impressive subcu data, are we even going to need an IV dose? I mean I know this is probably a little bit early to be looking into the crystal ball, but how do you foresee ultimately treating this disease, which is probably more heterogeneous than most people realize?

John Maraganore

It's a great question. Barry you want to handle it.

Barry Greene

Ted thanks for the question and the crystal ball into the future. It's fun to think about the issue of having two commercially available drugs for these patients. And as you know, our plan is develop ALN-TTR02 for FAP and ALN-TTRsc for the cardiomyopathy patients, FAC.

As we think about due to two commercial products available for all ATTR programs, it's likely in the future that we will generate data that allows these products to be used in the future interchangeably. With good data that allows us to educate the physician population to the appropriate use perfect dose and frequency of the drugs.

From a pharmacoeconomic perspective the diseases allow the kind of orphan pricings that you expect, so it won't be any economic incentive to change paces from one to the other, it really will be what's best for a patient. And as you fully appreciate in the world of orphan diseases, once we have and are benefiting the patient with the treatment of our drugs, we want to keep them on our therapies for the rest of their lives.

John Maraganore

And just to add to that, Ted, I suspect that in the future some patients will have to continue receiving drugs intravenous infusion. Like to go to the hospitals, with their physician to receive drug, and then other patients will say, well, I like the concept of having a at-home subcu option, and that's what I'd like to do going forward. And so I think we're going to create optionality here for patients in the future. And obviously, most importantly have what really is the best-in-class program, and best-in-class therapies available for these patients.

Ted Tenthoff - Piper Jaffray

I think there's a lot to learn, but I think you guys are making great progress, so really exciting.

Operator

Our final question comes from Stephen Willey of Stifel.

Stephen Willey - Stifel

I may have missed this, but just to confirm, the 7.5 mg/kg dose that you are planning to use in these next couple of cohorts, that's a single subcu injection, correct?

John Maraganore

Correct.

Stephen Willey - Stifel

And I know you also looked at retinal binding in vitamin A. Just any color around that? Is that consistent with what we have seen?

John Maraganore

Just totally beautifully consistent with what we've reported before. There is just a one beautiful correlation between [ph] RVT and vitamin A knocks down with TTR knockdown as well. So Steve, let me just also provide one clarification point. So we are doing 7.5 mg/kg weekly, okay. But we do, because of volume of administration we are using two injections to achieve that dose.

Stephen Willey - Stifel

And the volume, it's associated with each injection?

John Maraganore

It's roughly 1.5 ml for each injection of that dose. And so at 5 mg/kg, it could be done as a single 2 ml injection in that case.

Operator

And with no further questions, I would like to turn the conference back over to John, for any closing remarks.

John Maraganore

Well, thanks everyone for joining us this morning. We're obviously very excited about the new data and the potential for the continued execution of this platform in our Alnylam 5x15 strategy. And we look forward to sharing more updates and there will be more updates with you in the weeks and months to come. So thank you very much. Bye, bye now.

Operator

Ladies and gentlemen, this does concludes today's conference. You may now disconnect and have a wonderful day.

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Idera Pharmaceuticals (IDRA) announced on June 5th that it had initiated enrollment in a Phase 2 trial of IMO-8400, one of its lead drug candidates, for patients with mild to severe plaque psoriasis. The announcement was a bit more significant than many investors were aware of apparently, as there was little share price or volume response with only 127,250 shares changing hands that day. Buried in the announcement was the phrase announcing "Data from the Phase 1 study will be presented at a scientific meeting in June 2013." The data was indeed presented in June and subsequently announced on July 1st via a corporate press release. The data were promising in the single escalating-dose trial with multiple doses administered weekly for four weeks in healthy subjects. IMO-8400 was well tolerated at all doses with inhibition of TLR 7-, 8-, and 9-mediated cytokines, including tumor necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interferon-alpha (IFN-a), and other pro-inflammatory cytokines. Robert D. Arbeit, M.D., Vice President of Clinical Development noted in the press release that Phase 2 data will be available by the end of the year. The data release should be construed as significant and a large share price mover as Q4 winds down. Subsequently, it was noted in the company's Q2, 2013 10Q that the data will most likely be released in Q1, 2014. However, I believe share price movement will likely begin earlier as investors open long positions in anticipation of share price run up or in anticipation of possible positive data. Although the plaque psoriasis indication can be a significant market on its own, success in this indication could help to validate the program for other indications including lupus and other autoimmune diseases. Moving forward, I believe liquidity and investor interest should increase rapidly into November and December.

Idera is focused primarily on the treatment of autoimmune diseases via two candidates, IMO-3100 and IMO-8400. Although the company is in preclinicals developing candidates as vaccine adjuvants via collaboration with Merck, that part of the pipeline is still in its early stages and beyond the scope of this article. Idera's pipeline is attempting to address autoimmune disease by modulating immune response through Toll-like Receptors (TLRs). TLRs are part of the immune system that utilize pattern recognition (usually protein patterns) to recognize pathogens and damaged tissue. These TLRs then trigger an immune response against the perceived pathogens or damaged tissue via innate and adaptive responses. A large part of this immune response is via production of cytokines. Although effective, these cytokines can often be over-produced, produced unnecessarily, or can even target actual tissue, exacerbating already critical conditions. Idera is using knowledge that TLRs 3, 7, 8 and 9 are implicated in multiple autoimmune diseases such as lupus, psoriasis and arthritis to develop its two product candidates. It is employing IMO-8400 and IMO-3100 to inhibit or deactivate these TLRs in an attempt to stifle the autoimmune response. Success or perceived success in either of these two candidates could provide for much hope in these highly unmet or undermet indications (and markets).

Each of Idera's two clinical candidates is being evaluated initially to treat mild to severe plaque psoriasis. This autoimmune disease manifests itself via raised, red patches covered with a silvery white buildup of dead skin cells. The condition is a solid initial target indication as it is the single most prevalent autoimmune disease in the U.S. with about 7.5 million Americans affected according to the National Psoriasis Foundation. According to a recent article, sales of drugs addressing psoriasis in 2010 alone totaled $3.9 billion with expected growth to $7.4 billion by 2020, just 7 years from now. On December 19th, 2012 Idera announced topline data from its Phase 2 trial evaluating IMO-3100 to treat moderate-to-severe plaque psoriasis. Per the trial's design, 44 patients were randomized to receive IMO-3100 at 0.16 or 0.32 mg/kg or a placebo by subcutaneous injection once weekly for four weeks with four weeks of follow-up evaluation. The safety profile from the patient set was impressive with both doses being well tolerated with no treatment-related discontinuations. In terms of efficacy, results were promising with 48% of patients treated with either dose of IMO-3100 (12 of 25 patients) demonstrating improvements of 35% to 90% from baseline Psoriasis Area Severity Index (PASI) scores. None of the 12 placebo group recipients were able to experience such, with the treatment groups yielding a statistically significant (p<0.005) correlation. In the only negative bit of data from the trial, the trial achieved reduction in PASI scores at the end of treatment in the 0.16 mg/kg dose cohort with statistical significance (p<0.02) compared to the placebo cohort, but not in the 0.32 mg/kg dose cohort, indicating higher dosages of the drug did not increase the drug's effectiveness in the short term. However, at the end of the four-week follow-up period, 25% (3 of 12) of patients treated with 0.16 mg/kg dose and 31% (4 of 13) with 0.32 mg/kg dose achieved PASI 50 or greater, compared to none of the placebo patients. With solid safety profile on both dosages, both options will be available moving forward as the product is developed further.

With solid apparent success in IMO-3100 for the Phase 2 trial, IMO-8400 could generate even better data coming from its ongoing Phase 2 trial. IMO-3100 is an antagonist of TLRs 7 and 9, meaning that any autoimmune response that these two TLRs initiate could possibly be treated effectively. Meanwhile, IMO-8400 deactivates TLRs 3, 7, 8 and 9. If IMO-8400 deactivates TLRs 7 and 9 as well as IMO-3100, any additional deactivation of TLRs 3 and 8 should only add to the drug's efficacy relative to IMO-3100.

While looking forward to the early Q1 Phase 2 data release for IMO-8400, Phase 1 data as mentioned earlier indicated possible efficacy with a good safety profile already. Phase 1 data for IMO-3100, released on April 4th, 2011 gave investors an idea of the possible efficacy for the Phase 2 IMO-3100 data as noted above. Phase 1 IMO-3100 data was presented as "IMO-3100 was well tolerated in both treatment regimens. There were no serious adverse events and no treatment discontinuations. Mild injection site reactions were the most common adverse events." In terms of efficacy, the company noted "Suppression of multiple cytokines including IFN- a, IL-6, MIP-1B, and IL-1Ra, mediated through TLR7 and TLR9 was observed in both IMO-3100 groups." I believe investors could anticipate a comparable press release for the Phase 2 data on IMO-8400 and note that both drugs utilized dosages of 0.32 and 0.64 mg/kg twice per week.

Idera's common shares closed yesterday's trading day at $1.64, giving it a market capitalization of $74.3 million. According to the company's Q2, 2013 financials, it has capital sufficient to fund it through year-end 2014. However, the company announced after markets closed yesterday that it was performing a stock offering to fund its operations. With no dollar amount yet assigned to the offering and no share price indicated, I believe the offering could provide interested investors with a solid entry-level price for an exciting company that could be well-funded through 2014. Whether the company announces the terms of the offering very soon or later at elevated levels assuming positive Phase 2 data, I believe the company presents much upside potential for investors if data are promising. With Phase 2 data release for IMO-8400 an almost imminent event and additional Phase 2 trials for IMO-8400 in "other autoimmune disease indications, including lupus" set to begin enrollment also in Q4, I believe investor interest will be increasing rapidly and soon for this under-the-radar autoimmune company. Please note that this is a development-stage company with no real revenue generation at this point. Most of the value ascribed to the company's $74.3 million market capitalization is based on its early-stage pipeline success and its drugs' potential markets if approved for such. The investment is not for the risk averse and should be considered only after much additional due diligence.

Disclosure: I have no positions in any stocks mentioned, but may initiate a long position in IDRA over the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article. (More...)

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Agenus: Thoughts On Phase II Results For Prophage In Glioblastoma

Reason for This Report

Agenus (AGEN) just issued an update on a Phase II trial of Prophage G-100 combined with current standard of care in newly diagnosed glioblastoma patients that showed median overall survival (OS) of 23.3 months. There was no control group in the study but data from recent trials suggests that OS with standard of care (SOC) approximates 16.2 months. Standard of care is surgical resection followed by regimen made up of the cancer drug temozolomide and radiation.

This data suggests an improvement of 7.1 months in OS with Prophage G-100 versus SOC. As discussed in this report, an improvement in OS of four to five months is considered a significant advance for drugs like Prophage that are being tested in aggressive cancers such as glioblastoma. Importantly, temozolomide was approved for newly diagnosed glioblastoma on the basis of only a 2.5 month improvement in OS.

This was a small, non-randomized multi-center Phase II trial with 46 patients and it is not infrequently the case that promising results in small Phase II trials are not replicated in larger Phase III trials. Despite this caveat, this is a very encouraging signal of efficacy. Also, it is important for investors to understand that the Phase III trial in newly diagnosed glioblastoma is still in the planning stages so that results are several years away.

There has previously been a similar strong signal of efficacy in a trial of Prophage G-200 in recurrent glioblastoma; almost all patients die or have their disease recur in a three to four year period and about one-half die within 18 months. This earlier trial showed an improvement in OS of 2.5 months. Avastin was approved in the recurrent setting even though it showed no improvement in OS; the basis of its approval was shrinkage in tumor size in a small number of patients. A NCI sponsored randomized, placebo-controlled Phase II trial involving 222 patients is now underway in recurrent glioblastoma. If results substantiate a meaningful improvement in OS, this could be the basis for approval as early as 2015 or 2016.

The conventional wisdom on Wall Street is that cancer vaccines don't work. This is based on a long string of failed attempts to develop such products. The only cancer vaccine that has been approved is Provenge, which showed a 4.5 month improvement in OS in metastatic prostate cancer. I sometimes feel like Don Quixote tilting at windmills when I write positively on cancer vaccines. Others are enormously skeptical.

However, I remain undaunted. We have seen signals of efficacy similar to Prophage in three other glioblastoma cancer vaccines: Northwest Biotherapeutics (NWBO) DC Vax-L, ImmunoCellular's (IMUC) ICT-107 and Celldex's (CLDX) rindopepimut. It may be the case that encouraging findings in these three other products occurred by chance and that each product will fail in Phase III trials. This seems to be what most people think, but I am much more hopeful.

Let me anticipate the next question. Which of these products will win out if all are successfully developed in glioblastoma and approved? There is not enough data for me to try to answer this question. However, I think that past experience suggests that each product might work in some patients and not in others and that they would be used sequentially or in combination. I think that they would likely all do well in glioblastoma from a commercial standpoint if they are approved.

The really important point, however, is that cancer vaccine technology would be validated and would suggest applications in a broad, broad range of tumors. Cancer vaccines might be seen as a major advance in cancer therapy and each of these small companies would be viewed as leaders in the field. It is possible/probable that each would be acquired by Big Pharma companies before their products were ever introduced.

Investment Thesis for Agenus

Let me touch now on the investment thesis for Agenus. In my initiation report, I pointed out that Agenus has a broad portfolio of products in development. One of the two most important in the near term is the MAGE A-3 vaccine for metastatic melanoma and non-small cell lung cancer. This is a Glaxo (GSK) product that used Agenus's QS-21 as an adjuvant. However, the most important Agenus asset is probably the Prophage programs in newly diagnosed and recurrent glioblastoma, which remain wholly owned by Agenus.

The recent failure of the MAGE A-3 vaccine to reach one of its co-primary endpoints of disease free survival in metastatic melanoma touched off a sharp decrease in the price of Agenus. I pointed out at the time that there are several ways for investors to win with Agenus and I think that the recent news on Prophage in newly diagnosed glioblastoma illustrates this as the previous price decline was essentially reversed with the news on Prophage. The stock closed at $3.71 before the news on MAGE A-3 on September 5, 2013 was announced and the news caused the stock to decline to close at $2.84 the next day. The report on Prophage on September 17 led to an inter-day high of $3.68. However, the announcement later that day of a financing then drove the stock back to $2.98 or so.

I think that the potential for Prophage more than justifies buying the stock at current prices. However, there is also the potential that new data from the RTS,S malaria trial and the Phase II trial of HerpV in genital herpes could provide a new boost to the stock as results are expected before the end of the year.

I also advised in my last note not to write off the MAGE A-3 vaccine just yet. The trial in metastatic melanoma did not hit one of the two co-primary endpoints of disease free survival. However, the Independent Data Monitoring Committee unanimously recommended that the trial continue to the second co-primary endpoint. This is PFS in a prospectively identified sub-population in the trial that has a unique gene signature or profile. Results in this sub-population will be reported in 2015. There will also be OS data from the melanoma trial and results from the use of MAGE A-3 in non-small cell lung cancer reported in 2014. There are good arguments that PFS could be reached in non-small cell lung cancer. Refer to my report written on September 5, 2013 for a more detailed discussion.

Late Breaking News on Financing

Agenus just announced that it has issued 2.2 million shares and 650,000 warrants exercisable at $3.75 to raise $6.5 million. The Company had $13 million at the end of 2Q 2013 and has a current burn rate of $4 to $5 million per quarter. This new cash infusion suggests a year end cash balance of about $9 million assuming no new cash infusions. Agenus is clearly looking at the prospects for partnering HerpV or Prophage in late 2013 or early 2014 to make a meaningful contribution to covering the cash burn in 2014 and beyond.

Agenus now has 30.0 million shares outstanding, 3.7 million options, 3.3 million warrants and 0.5 million shares underlying non-vested shares and convertible preferred stock. Not all of the options and warrants are likely to be exercised, but for the sake of conservatism, let's assume that they are. In this case, Agenus would have 37.5 million fully diluted shares outstanding. Based on this and the recent price of $2.98 the fully diluted market capitalization is $112 million.

Update on Trial of Prophage in Newly Diagnosed Glioblastoma

Agenus reported updated data from a Phase II trial in 46 patients with newly diagnosed glioblastoma treated with a combination of Prophage G-100 and standard of care. The principal endpoints of the trial that investors focus on are median overall survival (OS) and median progression free survival (PFS). For those not familiar with statistics, the median is the numerical value separating the higher half of a data sample from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to highest value and determining the middle number, e.g., the median of the series of five numbers 1, 4, 5, 8 and 9 is 5.

This Phase II trial included 46 patients and the primary endpoint is median overall survival (OS). At this most recent look, the median overall survival was 23.3 months and the median progression free survival was 17.8 months. In this report I focus on OS because this is the primary endpoint of this trial and will almost certainly be the primary endpoint if a Phase III trial is conducted. Because this trial was not randomized with some patients given standard of care, patients treated with Prophage cannot be directly compared to a control group receiving standard of care. To put the results in perspective, we must look at results obtained with standard of care in other trials.

The standard of care in glioblastoma is surgical resection followed by a regimen of radiation and temozolomide. This was first defined in the Stupp trial whose results were published in the March 10, 2005 issue of the New England Journal of Medicine. The data from that trial showed that median overall survival for surgery followed by radiation and temozolomide was 14.6 months. This compared to 12.1 months in the group that only received surgery followed by radiation, the previous SOC. The accepted OS for SOC became 14.6 months, but this has since been revised upward.

In a May 9, 2009 issue of the Lancet, data on a subset of patients in the Stupp trial was presented. These were patients who underwent gross total resection that was enhanced by gadolinium imaging followed by radiation and temozolomide. In this group, OS was 18.8 months and this became accepted as the expected result for standard of care. Quite recently, Roche (RHHBY.OB) and the RTOG completed two large trials comparing Avastin added to standard of care in glioblastoma (more of this later). The median overall survival was 15.7 and 16.7 months for standard of care in these trials. Because the Avastin trials were very large trials that enrolled 637 patients in one trial and 921 in a second, I think that they are more accurate in defining OS for standard of care.

How Good are the Results?

I think that with some confidence we can assume that SOC or surgical resection followed by radiation and temozolomide leads to OS of about 16.2 months, which is the average shown in the two Avastin trials. Prophage G-100 is showing OS of 23.3 months which is a 7.1 month improvement in OS relative to standard of care. So, is that good or bad? Investigators generally consider a 4 to 5 month improvement in OS as being a significant advance. For example, the recently introduced Zytiga and Xtandi showed a 4 to 5 month improvement in OS in metastatic prostate cancer. In the previously reported Stupp trial, the improvement in OS attributable to temozolomide in glioblastoma was 2.5 months.

Viewed against these drugs, the 7.1 month improvement in OS demonstrated by Prophage in this patient group was extremely impressive. Of course, the next question is what this might mean in terms of commercial success? Following their introduction less than three years ago, Zytiga and Xtandi sales should reach about $1.5 billion and $400 million respectively in 2013. Because prostate cancer is more prevalent than glioblastoma, this only means that clinicians considered the OS results as significant and quickly incorporated them into their practices. However, temozolomide with a meager OS improvement of 2.5 months in glioblastoma went on to achieve peak sales of over $1 billion. This provides more insight on potential in glioblastoma.

Reported OS for Prophage Could Improve from 23.3 Months

In the current trial of 46 patients, 13 patients have died. Of the remaining patients who are alive, 9 are beyond 23.3 months of survival and 24 have not yet reached 24 months. Remember that median overall survival of 23.3 months means that of the 13 patients who have died, the median patient died at 23.3 months. This statistic changes with each additional death in the trial.

The history of immunotherapy is that it takes a while to take effect. It also seems to be the case that patients who respond to the therapy can experience some very long survivals. This was shown in the Phase I trials of Northwest Biotherapeutics' DC Vax-L and ImmunoCellular's ICT-107 in their Phase I trials. This was also seen with Bristol-Myers Squibb's (BMY) checkpoint inhibitor Yervoy. If this holds true with Prophage, I would expect to see the OS improve as more patients in the trial die. My expectation is that OS will improve from 23.3 months.

Prophage Results in Recurrent Glioblastoma are Also Encouraging

Agenus has previously reported encouraging results for Prophage G-200 in recurrent glioblastoma. In 2012, results from a trial of 40 patients given Prophage were reported. There was no control group in the trial, but results were compared to that for 86 consecutive patients not enrolled in the Prophage G-200 trial who were treated with alternative therapies during the study period.

The OS for Prophage was 10.9 months and the OS for the surrogate control group was 7.5 months for an improvement of 2.4 months. How good is this? One way of looking at this is that temozolomide only produced a 2.5 month improvement in newly diagnosed glioblastoma in which patients have a much longer expected survival time than those who suffer recurrences.

Another way of viewing these results is to look at Avastin, which is approved for recurrent glioblastoma. The package label for Avastin for recurrent glioblastoma states the following. The effectiveness of Avastin is based on improvement in the objective response (shrinking the size of the tumor). There is no data showing improvement in OS or PFS. There were two trials that supported approval; one showed an objective response of 19.6% in patients and the other showed 25.9%.

If the Prophage Phase II results in recurrent glioblastoma hold up, the improvement in OS of 2.5 months would be a major advance over Avastin, which has shown no improvement. Prophage G-200 is currently in a Phase II trial involving 222 patients. If the results are positive, this could be the basis for approval in 2015 or 2016 and would likely be the first cancer vaccine approved in glioblastoma.

More on the Recent Avastin Trials in Newly Diagnosed Glioblastoma

Roche recently reported results in two large Phase III trials of Avastin in newly diagnosed glioblastoma. RTOG 0825 was a 978 patient trial with 637 randomized patients. There was no improvement of OS, which was 15.7 months for Avastin as compared to 16.1 months for SOC. PFS of 10.7 months was an improvement versus 7.3 months for SOC. In the second trial, AVAglia there were 921 patients enrolled. The OS of 16.7 months for Avastin was the same as the 16.7 months seen with SOC. PFS was 10.6 months for Avastin versus 6.2 months for SCO.

Avastin has shown very modest efficacy, if any, first in recurrent glioblastoma and now in newly diagnosed glioblastoma. I would be shocked if the FDA approves it for newly diagnosed glioblastoma.

Disclosure: I am long AGEN, BMY, NWBO, IMUC. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article. (More...)

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Theravance's CEO Reviews Phase 2b Study 0091 with its LAMA Candidate TD-4208 Results - Transcript

Executives

Mike Aguiar - SVP & CFO

Mathai Mammen - SVP, Research & Early Clinical Development

Rick Winningham - CEO

Analyst

Anant Padmanabhan - Cowen and Company

Steve Byrne - Bank of America

Howard Liang - Leerink Swann

Stephen Willey - Stifel Nicolaus

Theravance, Inc. (THRX) Phase 2b Study 0091 with its LAMA Candidate TD-4208 Results Call September 4, 2013 8:30 AM ET

Operator

Ladies and gentlemen, good afternoon. At this time, I'd like to welcome everyone to the Theravance Conference Call. During the presentation, all participants will be in a listen-only mode. A question-and-answer session will follow the company's formal remarks. (Operator Instructions)

I will repeat these instructions after management completes their prepared remarks. Today's conference call is being recorded. And now, I would like to turn the call over to Mike Aguiar, Senior Vice President and Chief Financial Officer. Please go ahead, sir.

Mike Aguiar

Good morning, everyone, and thanks for joining us. As we discussed the positive top-line Phase 2b study results from a dose ranging 7 day crossover design Phase 2b study of TD-4208. An investigational long-acting muscarinic antagonist administered once-a-day as a nebulized aqueous solution in patients with moderate to severe chronic obstructive pulmonary disease.

With me on the call today is, Rick Winningham, our Chief Executive Officer, and Mathai Mammen, Senior Vice President of Research & Early Clinical Development. We've prepared a few brief remarks for today's call and then we'll open it up for questions.

A copy of the press release and slide presentation can be downloaded from our website or you can call Investor Relations at (650) 808-4100 and we will be happy to assist you.

Before we get started, we would like to remind you that this conference call contains forward-looking statements regarding future events and the future performance of Theravance.

Forward-looking statements include anticipated results and other statements regarding Theravance's goals, expectations, strategies and beliefs. These statements are based upon the information available to the company today and Theravance assumes no obligation to update these statements as circumstances change.

Future events and actual results could differ materially from those projected in the company's forward-looking statements. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the company's Form 10-Q filed with the SEC.

Before I turn the call over to Mathai, I would like to remind you that this slide presentation can be accessed from our website and the slide number referenced during the discussion can be located at the lower right corner of each slides. Additionally, we will not be answering any questions on the call today regarding next week's Advisory Committee Meetings on ANORO ELLIPTA as the briefing documents will be posted by the FDA in the next few days.

I'll now turn the call over to Mathai Mammen. Mathai?

Mathai Mammen

Thanks Mike. Good morning everyone and thank you for joining us. I'm very excited to review the results from the Phase 2b study with TD-4208. First by way of background TD-4208 was discovered as part of a major effort we had internally with the multivalent antagonist of the muscarinic receptor family with long receptor half lives. Beta antagonists were intend to have long-action in the lungs and be suitable for inhalation delivery.

The current goal of our LAMA program is to develop a once-a-day inhaled medicine in a nebulizer that offers improved efficacy and tolerability relative to current therapy. And that provides the bases for combination nebulized products with other medicines such as an inhaled corticosteroid. We believe the opportunity for nebulized product is significant and complementary to that addressed by the GSK Theravance collaboration products.

For some COPD patients current handheld devices are simply not suitable. For instance, some patients may lack the physical or mental dexterity to coordinate a single-breadth inhalation. Nebulization may be the preferred delivery mode for such patients. A strict requirement of the LAMA intended for nebulization is chemical stability in aqueous solutions a feature not common to many LAMA.

TD-4208 is a non-esters non-quaternary nitrogen compound that is chemically stable in aqueous solutions. We announced the results last year the single dose study in COPD patients with TD-4208 and ipratropium as an active comparator. As a reminder in that study TD-4208 was fast acting with the speed of onset comparable to ipratropium and demonstrated a significance and durable bronchodilator response using doses of 350 microgram and 700 microgram.

In the study we are reporting today 0091 we have replicated the evaluation of the original dose range together with lower doses in order to better understand the dose response relationship for TD-4208. For this reason we've included six doses over a 30 fold range from 22 microgram to 700 microgram delivered to patients using a well established standard PARI nebulizer device delivering a simple aqueous formulation.

Let's please turn to Slide 3 for a discussion of 0091. This Phase 2b study was a 7-day repeat dose study where every patient received placebo and four of the six dose group in an incomplete block design with a two week washout period between the five periods. The primary endpoint was predefined as a change from baseline in FEV1 trough after day seven dose. On day seven in all periods we collected serial spirometry from patients over the 24 hour period post-dose. The predefined primary endpoints was the change from base line in FEV1 trough on day seven. The key secondary endpoints were peak effect, area under the FEV1 curve or AUC and the weighted mean FEV1 again derived from the day seven spirometry. The weighted mean is an especially important secondary endpoint and is conceptually the average FEV1 change measured over the entire 24 hour period.

Please turn to Slide 4 where I'll summarize the efficacy data. Prior to doing that I first note that we analyzed the data very carefully for any evidences carryover effects from period-to-period and there were none. Now the data. I'm pleased to report that statistically significant effects were seen at all fixed doses studies from 22 micrograms to 700 micrograms. In other words the primary endpoint was reached for all doses study. The placebo adjusted FEV1 changes of trough ranged from 53 ml to 114 ml.

I'm equally pleased to report that we met all secondary endpoints for all six doses with weighted mean FEV1 ranging from 83 ml to 147 ml. We observed that the medium time to reach 100 milliliters improvement in FEV1 range from 30 milliliters to 60 milliliters.

Let's now look at Slide 5 for a deeper look at the bronchodilator responses over the range of doses study. Plotted on the left is the primary endpoint trough FEV1 on day seven verses dose. Plotted on the right is the key secondary endpoint weighted mean FEV1 on day seven versus dose. These two plots provide a comfortingly consistent picture. The placebo response was small. The two lowest doses of 22 micrograms and 44 micrograms provided a bronchodilator response but not likely to be a clinically meaningful one. The highest dose of 700 seem to offer no advantages over the next two highest doses. The dose of 175 microgram seems to be approaching the top of a dose response on these and multiple other measures. These doses are proprietary to rich information set from which we feel able to select the smaller range of doses for additional study.

Please turn to Slide 6. An additional objective of the study was to determine the likelihood that TD-4208 could be appropriately dosed once daily and not more frequently. All the preclinical data are consistent with the compound with an extended pharmacodynamic action in the lung as where the single dose clinical data reported earlier. The data from study 0091 continues to support once daily doses.

As stated previously we collected FEV1 at a number of time points distributed over the 24 hours at the last day of doses. It is instructed the first visually inspect the 24 hour placebo corrected serial FEV1 curves, which are shown here on Slide 6. One can see that the curves are generally flat across the 24 hour dosing in a row for all doses. One sensitive analysis is to look at the area under this FEV1 curve or AUC for the first 12 hours on day seven and compare this value to the AUC in the second 12 hours on day seven. For all doses study and is tabulated here the ratio of the two AUCs was very close to one for all doses meaning that almost all the treatment effects for the first half of the day was preserved in the second half of the day. There are multiple ways to analyze these data and to use data drawn from approved or late stage bronchodilator drugs at calibration. In general, the current data set provides further evidence that TD-4208 has the potential to be dosed once a day.

So in summary of the efficacy data 0091 we have first demonstrated a dose response for TD-4208; second, identified a dose range that is appropriate to include in future studies; and third, observed a constant bronchodilation response relative to placebo across the full 24-hour dosing interval, consistent with the compound that could be dosed once daily.

Now turning to Slide 7, I will summarize safety findings. As I will describe further in the slide to follow, treatment-related adverse events were comparable to placebo. There were no SAEs related to treatment and no discontinuations due to AEs related to treatment. A full review of all labs for all subjects in the study revealed no clinically significant signs. There were no increases in heart rate at any other time points for any of the doses studied related to placebo. There were no ECG changes including arrhythmias and QTc changes at any of the doses at any of the time point. All of these data are consistent with the very low plasma concentrations of TD-4208 measured in the study.

I will now elaborate on AEs on Slide 8. TD-4208 exhibited an AE profile at all doses that were comparable to placebo. Shown here are the tabulated treatment emergent AEs that occurred two or more times in the entire study. The overall percentages of patients reporting any AEs were about 18% on placebo and between 7% and 16% on TD-4208. The two most common AEs were headache and dyspnoea. Generally, TD-4208 was well tolerated in study 0091.

Now let's turn to the final slide. In summary, all doses in this Phase 2b program for TD-4208 met all primary and secondary endpoints providing significant and clinically meaningful bronchodilation at the higher doses. The 24 hour Serial FEV1 profiles are consistent with the once daily regimens. And finally the safety and tolerability of TD-4208 appeared comparable to placebo at the doses study. We look forward to continue to announce this for our new data set in planning next step.

I'd like to end by offering my sincere thanks to the Theravance team that conducted an excellent study and especially to the patients that participated.

And with that I'll turn the call over to Rick. Rick?

Rick Winningham

Thanks, Mathai. In summary, we are very pleased with these study results for TD-4208 a compound discovered and developed by Theravance. Looking forward, Theravance has a number of important events coming out during the remainder of 2013. These include next week's FDA Advisory Committee for ANORO ELLIPTA; potential RELVAR ELLIPTA regulatory events in other regions; Phase 2 results in ADHD for our dual norepinephrine and serotonin reuptake inhibitor; the producer date for ANORO and ELLIPTA in December; and finally the separation of Theravance into two publicly traded entities either late this year or early in 2014.

And now I'd like to turn the call over to the conference facilitator and open the call for questions.

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) We’ll have our first question from Anant Padmanabhan with Cowen and Company. Your line is open.

Anant Padmanabhan - Cowen and Company

I have a couple. First, I was wondering if you could discuss any market research you have and the demand for a nebulized LAMA. What percent of LAMA eligible patients do you think would need nebulized formulation? And then I have a follow-up.

Rick Winningham

Sure. It's a great question. Based on the research that we've conducted to-date in the current market that exist today in the United States, we would estimate between 5% and 10% of patients prefer a nebulized route of administration for the reasons that Mathai highlighted in his remarks.

Anant Padmanabhan - Cowen and Company

And then, could you discuss any plans to do a LABA/LAMA formulation as a nebulizer? And what would be the LABA in this case?

Rick Winningham

Yeah, no, not at this particular point in time I -- we don't have plans to do a LAMA/LABA combination. Yeah our LABA combination work is really focused with GSK. Mathai did highlight in a nebulizer work that we expect to do with an inhaled corticosteroid. So, I think there is an opportunity for that type of work but it's unlikely that we will take on LABA combination because of our agreement with GSK.

Operator

Our next question comes from Steve Byrne with Bank of America. Your line is open.

Steve Byrne - Bank of America

Mathai, can you talk about the dose response curve, is it logical to you that there could be a peak a dose response and that the higher doses some detrimental effect on FEV?

Mathai Mammen

No that wouldn't be physiologically expected or consistent with the behavior antagonist. My expectation is that if you look at from based on all of the published LAMA dose response type data that's out there that these antagonists have a quite a rough dose response curve. We're actually quite pleased that the very low doses as I said in the prepared statements have a minimal effect and the higher doses generally have or somewhere on a max effect. And I explained the kind of ups and downs of the higher doses as noise within the population relatively small set.

Mike Aguiar

Yeah, Steve, this is Mike. I think if you look at a lot of the data here and compare and see with the UMEC data for example it's just not typical to see a really robust very clear dose response curve with the muscarinic antagonist that's not necessarily the way they behave. So I just would reiterate what Mathai said which is we're awfully pleased to see lower doses where there with the level of efficacy albeit below clinical significance so that would clearly find the lower end of where would be looking and then to have several doses that were clinically relevant. So we did exactly what we want it but again I just would not expect the kind of your traditional a highly linear type dose response curve with these compounds that's not really what is seen in the clinics today.

Steve Byrne - Bank of America

Then can you comment on this 114 milliliters of trough FEV how would that compared to the say standard-of-care?

Mathai Mammen

I think the absolute efficacy is highly dependent on the population we see for example with Spiriva there is studies where Spiriva looks to have a 70 milliliters and other studies where it's about 140 milliliters, 150 milliliters. So my own contention is that LAMAs have an efficacy that's quite comparable among the LAMAs and where they actually play out the choice of therapeutic doses dictated by systemic, side effects, tolerability and safety. And so here we were pleased to see that even if the higher doses we had excellent safety and tolerability. So I think we'll be able to get to a place where we'll be able to get all one can out of this mechanism.

Steve Byrne - Bank of America

And Mathai, can you just talk about where you want to go from here with the clinical developments that you've need to do more dose ranging before you go into Phase 3?

Mathai Mammen

So I think that we're -- we've just uncovered the dataset right now and we're looking carefully at the full set of data. I think we've chosen to report top-line here. We need to discuss internally exactly what we would do next before Phase 3. And I'll also note on the previous question one of the features of this compound that we did note at all doses is a very flat dose response curve. So even at the low doses there is very flat dose response curve so that is especially appealing to that.

Operator

(Operator Instructions) Our next question comes from Howard Liang with Leerink Swann. Your line is open.

Howard Liang - Leerink Swann

Will you need to look at the BID dose to show that's split dose BID is the same as QD at twice-a-dose?

Mathai Mammen

Currently the division in the U.S. regulators do ask for a formal QD BID study. So we're not able to say from the current dataset that we're definitively a QD dose drug but we're projecting that it looks pretty good. The flatness of our dose response curves we would project a reasonable chance in a formal QD BID study.

Rick Winningham

Yeah, Howard, it's a great question. I think because of the flatness of the curve over 24 hours that at multiple doses because of the ratio of effect of the second 12 hours to the first 12 hours approaching one, I think this would be a compound that I'm not too concerned about relative to on a twice-a-day versus once-a-day study. I mean, I think we'll have to get into more of the data but based on what we've seen today I think we are pretty confident in the once-a-day profile of this drug so much though that we would necessarily hold up any advance studies based on the completion of that type of a program we would likely do it concurrently with advanced studies.

Howard Liang - Leerink Swann

So and may be you can talk about strategically what you would intend to do with its compound do you eventually want to market it yourself and also and what the requirement of Phase 3 program for something like this to be similar to other COPD drugs in terms of the scope of the program?

Rick Winningham

Yeah. So I think the Phase 3 program likely for a nebulized compound would be similar to other single agent long-acting muscarinic antagonist. I think it's not the Phase 3 program is not overwhelmingly burdensome here for a nebulized product and we do see an opportunity in 5% to 10% of the COPD population that's very complementary to what we're doing with GSK. Where we go some here in terms of partnership I think we'll leave that open right now. I think we're very excited that we've got a drug here it's got a very good profile it behaved exactly as it was designed to do in the discovery program and I think whether we get a partnership whether we do further studies on our own that's sort of yet to be decided.

Operator

Our next question comes from Stephen Willey with Stifel. Your line is open.

Stephen Willey - Stifel Nicolaus

Yeah. Thanks and forgive me if you've already covered this in early part of the call. I think you had made some prior comments I think around once you had confirmed the TD profile of the drug that you would then potentially had some reformulation options as either DPI or an MDI. And I'm just trying to think about it whether or not you guys are bent on just going forward with nebulizer only or would you potentially explore some of these other administration opportunities?

Rick Winningham

No, Stephen, that's correct. The form of the product the physical characteristics of the product support development in nebulizer but also in a DPI or an MDI we have that work ongoing it needless to say it's not as advanced as a nebulized form but we have that work ongoing in the physical properties that compound supported. So overall 4208 were quite broadly excited about what about what this may mean for the future of the company.

Stephen Willey - Stifel Nicolaus

So would you potentially look to explore parallel development pathways whereby you could have both a nebulized formulation and a DPI formulation in development at the same time?

Rick Winningham

Well yeah I think we would explore that I think it's unlikely we would take simultaneous Phase 3 programs as an example and in both the DPI and a nebulizer. But as we gain more confidence with the product in this for me was a critical study in which to gain significant confidence. The work that we put into the DPI and the MDI will increase because of the confidence generated from the study.

Stephen Willey - Stifel Nicolaus

And then just in terms of commentarial opportunities on the collaborative of the strategic firm. I know that there is really not a whole lot of available once daily LABA assets that are out there. I know that you said you weren't going to pursue that well but may be just give us a little bit color in terms of the once daily ICS assets that would be out there strategically or at least that are out there in development?

Rick Winningham

Yeah, I mean I think the assets that are out there or I didn't really don't want to go into a lot of detail on them because I think that's somewhat of a competitive advantage for us in keeping some of that quite. But suffice to say albeit that there are and I think we've seen opportunity with the LAMAs to combine with the potential steroid of a similar duration.

Stephen Willey - Stifel Nicolaus

And then if I could just ask just one quick ANORO question if you don't mind. Have you guys been pretty to all that subpopulation data that I guess GSK claims is used to support the approval of the higher dose?

Mike Aguiar

Yeah, Stephen, this is Mike. I don't want to get too far up here right now with ANORO commentary just because we've got briefing docs that will be posted here in a sort of eminently. So I'm going to punt on any ANORO questions right now. I would just say we remain confident in our dataset and I really wouldn't want to go beyond that right now again the data will be out in a very short order and we'll get a chance to discuss this soon for public view on Tuesday of next week. So I'll punt on that question for now.

Operator

Thank you. It appears we have no further questions on the phone. I'd now like to turn the call back over to Mr. Winningham. Please go ahead, sir.

Rick Winningham

Yeah, thank you very much. I'd like to thank everyone for joining us this morning with us to share this important news and we look forward to providing further updates on Theravance as the year progresses. Have a great day.

Operator

This does conclude today's conference call. We thank you for your participation. You may now disconnect.

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Isis Pharmaceuticals' CEO Discusses the ISIS-APOCIII Rx Phase 2 Monotherapy Data (Transcript)

Executives

Stanley Crooke - CEO and Chairman

Daniel Gaudet - Dept of Medicine, Université de Montréal and Scientific Director of the Genome Quebec Technology Center and Biobank

Richard Geary - SVP of Development

Lynne Parshall - COO

Walter Singleton - CMO

Wade Walke - VP of Corporate Communications and Investor Relations

Analysts

Eric Schmidt – Cowen and Company

Stephen Willey - Stifel, Nicolaus & Company

Jim Birchenough - BMO Capital Markets

Andrew Goldsmith - Canaccord Genuity

Ted Tenthoff - Piper Jaffray & Co.

Isis Pharmaceuticals, Inc. (ISIS) ISIS-APOCIII Rx Phase 2 Monotherapy Data Conference Call September 3, 2013 11:30 AM ET

Operator

Welcome to Isis Pharmaceuticals conference call to discuss ISIS-APOCIII Rx Data. Please note that this event is being recorded. Leading the call today from Isis is Dr. Stan Crooke, Isis Chairman and CEO. Dr. Crooke, please begin.

Stanley Crooke

Good morning everyone and thank you for joining us on today’s webcast. The purpose of the webcast is to discuss the results of an interim analysis of the third set of Phase 2 data on ISIS-APOCIII Rx, our triglyceride-lowering drug. Dr. Daniel Gaudet, a principal investigator in this study presented these data this past week at a PACE meeting session that occurred concurrently with the European Society of Cardiology Congress, in Amsterdam.

Our study is fully enrolled and it is still ongoing and we’re encouraged by the data we’ve observed thus far. The analysis reported this last weekend by Dr. Gaudet at this meeting of physicians in Europe is a midpoint interim analysis with 28 patients who have completed 13 weeks treatment. We will have the full data from this study as well as additional data from our APOCIII Rx program in November at the American Heart Association meeting.

We will also present additional Phase 2 data on ISIS-APOCIII in patients with familial chylomicronemia or FCS on September 21st at the National Lipid Association meeting. So the next good information that you will be getting about APOCIII Rx is actually before the AHA and at the NLA meeting in just a couple of three weeks and that will present the chylomicronemia data, the data in patients with FCS. So we hope that you will join us for all these presentations.

Slide 2, just shows the participants, Lynne Parshall, Chief Operating Officer; Rich Geary, Senior Vice President of Development; Walter Singleton, Chief Medical Officer and Vice President of Development; and Wade Walke, Vice President of Corporate Communications and Investor Relations and our special guest Dr. Daniel Gaudet, Scientific Director of the Genome Quebec Technology Center and Biobank and the principal investigator on this study we are reporting today, all of these people are joining me.

Slide 3, shows the agenda for our webcast. Richard will begin the discussion with a quick introduction of ISIS-APOCIII Rx. Dr. Gaudet will present the data from the Phase 2 study he presented on Saturday. Richard will then discuss the design and the results of our overall Phase 2 program to date and then after that I will close the call by discussing the next steps for ISIS-APOCIII Rx and of course we will it up for questions.

Now Wade will you read our forward-looking language statement please?

Wade Walke

Thank you, Stan. As a reminder to everyone, this webcast includes forward-looking statements regarding the discovery, development, and potential of drugs for cardiovascular diseases, and the development, activity, therapeutic potential and safety of ISIS-APOCIIIRx.

Any statement describing Isis’ goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of ISIS-APOCIII Rx, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs.

Isis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis.

As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2012, and its most recent quarterly report on the Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.

Now I will turn the call over to Richard.

Richard Geary

Thanks, Wade. Today we will present another set of data from the Phase 2 program on our triglyceride-lowering drug ISIS-APOCIII Rx. What we’ve seen from this drug across all the studies to date is remarkably consistent. These data confirm and bolster our earlier observations that one, ISIS-APOCIII Rx is a very effective triglyceride-lowering drug, which shown that it is equally effective in combination with fibrates and as a single agent.

Two, we get comparable reductions of triglyceride irrespective incoming triglyceride levels and this is important because other triglyceride-lowering drugs tend to work less well in patients with severely high triglycerides. Three, we’ve also shown that ISIS-APOCIII Rx has a positive impact on other lipid parameters measured. It raises HDL, lowers other atherogenic lipids such as apoC-III containing VLDL without raising non-HDL.

Four, it has also shown improvements in multiple measures of glucose control and consistent trends toward enhanced insulin sensitivity in patients with high triglycerides and type 2 diabetes. And finally five, in all studies to date the drug has been generally safe and well tolerated.

The most important new observation from the study reported this weekend is that ISIS-APOCIII Rx is showing good efficacy as a single agent in patients with very high to severely high triglycerides. This is an important finding because the initial indications we’re pursuing for this drug are in patients with severely high triglycerides, in other words, triglycerides higher than 880 mg/dL.

In Slide 6, there are approximately a 100,000 patients in the U.S. and Europe, who have severely high triglycerides despite currently available triglyceride-lowering therapies including diet. We believe that ISIS-APOCIII Rx may play a meaningful role in the treatment of these patients who remain at significant risk of cardiovascular disease, pancreatitis and many of whom have other serious comorbidity such as diabetes or metabolic syndrome.

Standard therapies on the market today like fibrates are not able to lower triglyceride sufficiently in these patients to bring them to recommend at triglyceride levels. Because of the lack of truly effective therapies, these patients are very much in need of new treatment options.

apoC-III as a remainder as a genetically validated target is well understood, lower levels of apoC-III are associated with favorable lipid profiles as well as enhanced health and longevity. These data are evident when you look at so called experiments of nature in which due to genetic differences three different well studied human populations have apoC-III levels with their either lower or higher than normal levels.

The first two populations Ashkenazi Jews and Old World Amish have mutations in the apoC-III gene that leads to lower levels of apoC-III. Because of their low apoC-III levels these people experience many favorable health factors such as reduced triglycerides, reduced blood pressure, reduced atherosclerosis and improved insulin sensitivity and a longer life span.

In contrast, a population of Asian Indian men who have apoC-III levels that are higher than normal have high triglycerides and a higher incidence of cardiovascular disease as well as nonalcoholic steatohepatitis liver and insulin resistance.

We believe that ISIS-APOCIII Rx can be used as a single agent or in combination with existing drugs, used to treat patients with high triglycerides. The data we’ve reported this summer, gives us confidence that ISIS-APOCIII Rx could be an effective treatment for patients with severely high triglycerides and supports our enthusiasm for this drug.

Slide 9, summarizes our Phase 2 experience to date. We’ve observed significant reductions of triglycerides in apoC-III with a majority of patients in the 300 mg dose cohorts of each study achieving triglyceride levels below a 150 mg/dL. This is pretty remarkable when you consider that the patients who entered the study we’re reporting today at an average incoming triglyceride level of 660 mg/dL.

We are also very encouraged by the effect by ISIS-APOCIII Rx on the overall lipid profile on these patients. Not only did treatment with ISIS-APOCIII Rx significantly reduce apoC-III in triglycerides, but it substantially raised HDL, the good cholesterol without increasing non-HDL. In these studies we’ve patients with incoming triglycerides ranging from 187 mg/dL to 1,822 mg/dL.

The effects we observed on triglycerides were irrespective of incoming triglyceride levels and we observed consistent reductions in triglycerides in all of these patients. We also observed improved measures of glucose control and consistent trends toward improving insulin sensitivity and patients with high triglycerides in type 2 diabetes and of course we’re very encouraged by the safety and tolerability profile of the drug in these studies, particularly what we’ve observed in our 300 mg dose, the dose we’ve selected as our Phase 3 dose.

And now I’d like to turn the call over to Dr. Gaudet to walk us through the interim monotherapy analysis that he presented this weekend in which have to study participants, about 28 patients -- exactly 28 patients have reached the primary endpoint at 13 weeks.

Dr. Gaudet is the Scientific Director of ECOGENE-21 clinical trial center in Genome Quebec Biobank Technology Center. He is also one of the founders of the Lipid Metabolism Research Clinic, which he has been managing for several years now at Chicoutimi Hospital. He is Associate Professor of Medicine at University of Montreal and has been chair holder of the Canada Research Chair in preventive genetics and community genomics since 2001. Dr. Gaudet has led integrated clinical and research activities in the field of genetics, especially with regard to lipid metabolism disorders and their associated risks for some 20 years.

Over the years he has coordinated some 160 trials and academic projects involving the development of new drugs and technologies. He was an important investigator involved in the development of KYNAMRO and is the lead investigator for both the fibrate combination study and the monotherapy study in patients with high to severely high triglycerides we’re discussing today.

So now I’ll turn the call over to Dr. Gaudet.

Daniel Gaudet

Thank you, Richard. On Slide 11, we see the study designed of the multicenter randomized double-blind placebo controlled study involving 85 patients overall and as Richard said, we’re actually completing the analysis of this study and the interim results will be presented today.

This study was designed to demonstrate that the ISIS-APOCIIIRx can decrease TG and apoC-III levels. It was also evaluating the effect of this medication on overall lipid profile and post-prandial metabolism including TG rich lipoprotein characteristics, [on the micro clearance] and kinetics.

In this study there were two cohorts. The first one was an add-on to fibrate cohort, involving patients with triglyceride levels above 225 and below 2,000 on top of fibrates. This cohort involved 28 patients. The second cohort was in on monotherapy with patients having very high triglyceride levels of up to 440 and again below 2,000. This cohort involved 57 patients. After running period, these patients were randomized on either antisense drug the 100 mg, 200 mg or 300 mg weekly or placebo we treated for 13 weeks and then followed for an additional period of 13 weeks. The efficacy analysis presented today included 28 patients who completed 13 weeks of treatment. Safety data includes all patients exposed to the drug.

On Slide 12, we see here the baseline characteristics for only the patients who were included in the efficacy analysis from the different dose group in the monotherapy cohort. The dose groups overall were reasonably well balanced for all key baseline characteristics. Average triglycerides were very high, which range from [505] to 655 mg/dL with individually high as 1,822 mg/dL sort of range.

On Slide 13, all three doses produced no dependent significant reduction in apoC-III up to 79% in this study, which is consistent with the response were observed in the all of these studies to date. Again, here these are results of interim analysis and the study is still ongoing.

On Slide 14, the treatment with ISIS-APOCIIIRx produced remarkable dose dependent reductions in fasting triglyceride that was statistically significant of all doses with reduction of up to 75%. This is observed in both per percentage and illustrated in the bottom panel in milligrams per deciliter.

Slide 15 shows that the treatments with ISIS-APOCIIIRx also produced remarkable dose dependent increases in HDL cholesterol that was statistically significant for both the 200 and 300 milligram dose cohorts with increase of up to 57% the bottom lined on back of the placebo group.

Slide 16 now. On this slide we see the results for the 300 milligram dose compared to placebo. This comparison shows that the favorable effect of ISIS-APOCIIIRx on multiple lipid parameters. The 300 milligram dose has been selected as the dose that Isis will use in the Phase 3 studies. There were no adverse changes in ApoB and our non-HDL cholesterol.

On Slide 17, this slide shows baseline and of treatment values as well as percent reductions for the key lipid parameters. Note the range of the values, post treatment range in particular almost all patients – not almost, all patients were – there were no non-responders, all patients responded very well with a range between 105 and 152 for triglyceride, which was quite impressive here. Till now there were no non-responders and again we’re presenting interim analysis that is very, very impressive at this point. To reiterate, this large and statistically significant reduction in triglycerides, and after we changed a bit a significant increase in HDL as well on both VLDL cholesterol and HDL cholesterol and total lipid will be -- the efficacy was very, very, very important.

Slide 18, compares the effect of the 300 milligram dose on the key lipid parameters across the different cohorts in the Phase 2 studies. First column illustrates the results obtained in the single agent diabetes. Second column, in the single agent in very high TG and in third column the add-on cohort results. If there is a very important consistency in the reduction obtained in VLDL ApoC-III, total ApoC-III and triglyceride level as well as the increase in the HDL cholesterol in all these studies. There were no adverse change in non-HDL cholesterol and overall again these interim analysis shows pretty consistency -- important consistency across the studies.

On slide 19, in terms of safety, after 12 - 13 weeks of treatment, there were no related serious adverse events or significant adverse events. There were no treatment-related liver enzyme elevations. No abnormalities in the renal function or no clinically meaningful changes in other laboratory values. In term of tolerability there were no flu-like symptoms and very infrequent and predominantly mild injection site reactions. Those two last symptoms or signs are more related to the apoC-III therapy than to the (indiscernible) ApoC-III of the target.

On Slide 20, conclusions from the monotherapy study in patients with high to severely high triglycerides shows dose dependent and significant, rapid and robust durable reductions in triglycerides of approximately 75% and ApoC-III of approximately 79%. The treatment improved overall lipid profile, including the decreased triglycerides, VLDL-ApoCIII, ApoC-III, and the atherogenic lipid particles such as apoB and a -- the non-HDL cholesterol. HDL cholesterol significantly increased and the drug was generally safe and well tolerated in the patients who have been treated till now.

Now let me turn the call over to Richard again.

Richard Geary

Thanks, Dr. Gaudet. I will spend the remainder of the call reviewing the mechanism of apoC-III and then summarizing our Phase 2 experience to date with APOCIII Rx.

First as a reminder, the apoC-III protein is synthesized principally in the liver and upon secretion from the liver is associated with apoB containing atherogenic lipid proteins, VLDL and LDL and also HDL. And when apoC-III is associated with VLDL, it essentially inhibits the movement of triglycerides from VLDL and LDL to HDL. So if you decrease apoC-III, you would expect to both decrease serum triglyceride levels and shift triglycerides from VLDL and LDL to HDL. Both apoC-III and high triglycerides are validated independent risk factors for cardiovascular disease.

The cartoon on Slide 23 illustrates how apoC-III may inhibit the clearance of triglycerides from blood. apoC-III associates with lipid proteins in blood and acts as a brake or suppressor for lipoprotein lipase, the enzyme that causes degradation of triglycerides, illustrated here in the upper left hand side of the slide. The suppression of apoC-III synthesis with ISIS-APOCIII Rx in patients with high triglycerides should improve triglyceride clearance thereby improving peripheral energy supplies and increasing triglycerides as illustrated here in the upper right hand side of the slide.

We’ve conducted two randomized double-blind placebo controlled studies in patients with high triglycerides -- very high triglycerides and severely high triglycerides. We evaluated the effect by ISIS-APOCIII Rx in patients with high triglyceride and type 2 diabetes. We also evaluated the effect of APOCIII Rx both as a single agent and in combination with fibrates.

On slide 25, we have the design of the first study we reported in June at the ADA meeting. This was a randomized double-blind placebo controlled study in patients with high triglycerides and moderate type 2 diabetes in which we compared treatment with placebo to the effects of treatment with 300 milligram per week of APOCIII Rx for 13 weeks.

Slide 26, shows the remarkable effects of ISIS-APOCIII Rx on the overall lipid profile of these patients. Notice that the patients treated with APOCIII Rx achieved an 88% reduction of apoC-III and a 72% reduction of triglycerides. Treatment with the APOCIII Rx also resulted in a 40% increase in HDL or the good cholesterol.

On Slide 27, make the final important observations from this first study relate to insulin sensitivity and diabetes. Treatment with ISIS-APOCIII Rx improved multiple measures of glucose control, including glycated albumin and fructosamine and hemoglobin A1c. We also observed consistent trends toward enhancing insulin sensitivity. This if confirmed represents an important profile enhancement for ISIS-APOCIII Rx because patients with severely high triglycerides, our first indication, are frequently diabetic or prediabetic.

On slide 28, is the design of the second study we conducted on ISIS-APOCIII Rx. This was a randomized double-blind placebo control study with two separate cohorts. The first cohort was in patients with high to severely high triglycerides for 225 to 2,000 milligrams per deciliter despite treatment with fibrates and this cohort was designed to treat patients who were on stable doses of fibrates that will maintain throughout the study for 13 weeks with once either with once weekly placebo or 200 milligram or 300 milligram of ISIS-APOCIII Rx.

The second cohort in this study was the one described today by Dr. Gaudet. These were patients with very high or severely high triglycerides keep treated with APOCIII Rx as a single agent.

Slide 29 shows the results from the APOCIII Rx fibrate combination study. Here we see that in the 300 milligram APOCIII Rx cohort, APOCIII Rx reduced on average apoC-III by 70%, triglycerides by 64% and apoC-III containing VLDL by 77%. It also on average increased HDL by 52%. Importantly there was no significant effect on non-HDL cholesterol even when ISIS-APOCIII Rx was added to fibrates, producing the optimal changes in the lipid profile that these patients need. It lowers atherogenic risk factors and increases good cholesterol.

On Slide 30, which Dr. Gaudet also reviewed, we highlighted the effect of treatment with ISIS-APOCIIIRx on all three patient population studied. In this slide we highlight a 300 mg dose, as this will be the dose we plan to use in our Phase 3 program which we are on track to start early next year.

As you can see in this slide, treatment with ISIS-APOCIIIRx consistently reduces apoC-III, Triglycerides, apoC-III associated VLDL complexes and increases HDL with a positive effect on non-HDL. So I hope you can see from this slide why we are so encouraged with the performance of ISIS-APOCIIIRx and why we have chosen the 300 mg dose to move forward.

Slide 31, summarizes our overall experience with ISIS-APOCIIIRx and its quite remarkable that we observed consistent Triglyceride in apoC-III lowering in across all patient population studied. In all three data sets we observed improvements in the overall lipid profile of these patients including substantial increases in HDL without increases in non-HDL. These results were similar when used as a single agent or in combination with fibrates and similar irrespective of the incoming triglyceride levels of the patients. In fact 86% of the patients treated with 300 mg of APOCIIIRx in a Phase 2 studies to date achieved triglyceride levels less than 150 mg/dL. We also observed positive effects on glucose control and trends toward improved insulin sensitivity.

Slide 32 summarizes the overall safety profile of ISIS-APOCIIIRx across Phase 1 and the three patient population studied to date including all patients enrolled in the ongoing monotherapy cohort. We are very encouraged by the safety profile of the drug today. There have been no drug related elevations of liver enzymes greater than three times the upper limit of normal even when added to stems or fibrates and no clinically meaningful changes in renal function, no clinically meaningful changes in other biochemical or hematological laboratory values. And the drug has been well tolerated.

The most important AE and our most common AE has been in frequent injection side reactions that were predominantly mild in nature. In fact there have been no discontinuations due to ISRs and we also have not observed any flu like symptoms associated with drug treatment. In fact investigator feedback has been quite positive. What Dr. Gaudet has told us that in his experience the local reactions are in general very minor, and for the majority of the patients their experience with ISIS-APOCIIIRx is very positive. This improved tolerability profile we have observed with ISIS-APOCIIIRx is consistent with other newer second generation antisense drugs we have been reporting.

And now I’d like to turn the call back over to Stan.

Stanley Crooke

Thanks Richard. Slide 34, I think all the data from our Phase 2 program that we’ve presented this summer supportably for ISIS-APOCIIIRx is potentially a very attractive commercial asset. ISIS-APOCIIIRx addresses an important unmet medical need in patients with multiple health issues caused in part by high triglycerides. The most important aspect of ISIS-APOCIIIRx in the extend of triglyceride in apoC-III lowering of produces and this is unprecedented. It also has a positive impact on the overall lipid profile significantly raising HDL cholesterol. It may also provide benefit to many of these patients who also have diabetes or are pre-diabetic. Finally it can be used in combination or with existing therapies and that means it doesn’t have to displace any existing therapy to be commercially successful.

We have one more element of the Phase 2 program that we’ll be sharing with you at the National Lipid Association meeting on September 21st. At this meeting we will present Phase 2 data from a study in patients with familial chylomicronemia or FCS. For those of you who don’t know about FCS. FCS is a very rare ultra-orphan genetic disorder. There are about 3000 to 5000 patients worldwide with FCS. So you can think of it very much like almost like SFH, a disease you’ve become much more familiar with. The disease is usually the result of the genetic defect that leads to lipoprotein lipase deficiency and this in turn leads to a decrease in breakdown in clearance of triglycerides from the blood. Lipoprotein lipase is the enzyme that’s inhibited by apoC-III and these patients have very severe disease with triglycerides frequently in excess of 2000 mg/dL. We do look forward to sharing these data with you now I guess in just two -- little more than two weeks.

Then at the end of the year in November at the American Heart Association meeting in Dallas, Rosanne Crooke, the Head of the Cardiovascular Program at Isis in an invited presentation we’ll present more detailed summary an update of the entire Phase 2 experience with this drug. So we hope you’ll join us for those two presentations on ISIS-APOCIIIRx. We’re now working with experts to finalize our Phase 3 plan since we’ve prepared to meet with regulators in the U.S. and EU. Once we have our end of Phase 2 meetings we plan to share more detail about the upcoming Phase 3 programs which we plan to begin early next year. And just as a parting reminder ISIS-APOCIII is a drug that we own. As I mentioned we plan to begin our Phase 3 program for this drug early next year which sets us up for a potential regulatory filing in 2016, 2017 and of course we look forward to keeping you apprised of all the progress that we’re making in this program as well as our other programs.

And with that I’ll bring the conversation to a close and open this up for question. Amy if you can set us up please.

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) Our first question is from Jim Birchenough with BMO Capital Markets. Hello Mr. Birchenough, are you there? Hello Mr. Birchenough have you placed your phone on mute? Our next question is from Eric Smith with Cowen and Company.

Eric Schmidt – Cowen and Company

Thanks for taking my question and thanks for the call today. Maybe for Rich or Stan just trying to get a little bit more insight on your thinking for the Phase 3 program, you have been consistent in saying that you’re going to go after patients above 880 mg/dL triglycerides. I assume that’s on maximum triglyceride lowering background therapy that number?

Stanley Crooke

It will be probably all comers will – as we’ve learned that the vast majority of these patients come in with on no drugs, but we will allow people to be on their maximum tolerated drug and I would -- but I would still expect probably 70% or more of the patients will be on no drug at all.

Eric Schmidt – Cowen and Company

And Stan, did you have such patients above 880 in this trial who were on apoC-III and did they perform just as well as sort of the means?

Stanley Crooke

Yes. We’ve seen no difference in response irrespective of incoming triglyceride or irrespective of whether the patients are on a fibrate lowering drug. Now in this monotherapy study of course we didn’t allow anybody to be kicking any drugs, but you recall we reported on the fibrate data earlier.

Eric Schmidt – Cowen and Company

Okay. So you know you don’t have a lot of patients above 880, it would seem you’re still comfortable going right into a Phase 3 from a safety efficacy standpoint in that population?

Stanley Crooke

Absolutely. We have -- if you have a look at the – if you were to for example look at a dot plot of percent reduction or absolute reduction of triglycerides is a function of incoming triglycerides just linear or next close to linear as you would expect. And so we’re very, very, very confident at levels up to 2000. We see a very significant reduction’s that are consistent with the numbers that we’ve just shown here.

Eric Schmidt – Cowen and Company

Okay. And there wouldn’t be any FDA requirement first time or greater sample size, of patients in that range in Phase 2?

Stanley Crooke

Well I won't speak for the FDA until we go talk to them, we don’t believe so.

Eric Schmidt – Cowen and Company

And what's your latest thinking on how many patients you’ll need to treat at greater than 880 to get approval?

Stanley Crooke

Richard, maybe you can respond to that.

Richard Geary

Yeah, I think the thought and it's consistent with the advice that we’ve gotten in Europe about a year ago is that a study of about 100 patients that are randomized and to control and active treatment treated over a year is probably what's going to be needed and then all of those patients would be going into open label, and that’s consistent with the advice we received from EEU and we’ll be presenting that to the FDA.

Eric Schmidt – Cowen and Company

Okay, but that would also …

Stanley Crooke

We’ve been told about safety database is pretty much what you would expect for a population in the 50,000 range in each area and of course that’s all focused on the 880. We’re not commenting today on this ultra rare orphan disease the FCS patients, that would be a different matter altogether.

Eric Schmidt – Cowen and Company

So FCS would not be included in the Phase 3. Do you exclude them or just not now?

Stanley Crooke

No, I mean that the number required for an FCS indication would be dramatically smaller.

Eric Schmidt – Cowen and Company

Right; and would you exclude those patients from the Phase 3 or might they show up and just not be detected?

Stanley Crooke

What I would rather do is delay commenting on that until the 21st. We will be reporting Phase 2 data on patients with FCS on the 21st of September and at that point then we can begin to discuss that indication in more detail, all right.

Eric Schmidt – Cowen and Company

Okay. Thanks for answering all my questions.

Stanley Crooke

Good luck.

Operator

The next question is from Stephen Willey with Stifel. Go ahead please.

Stephen Willey - Stifel, Nicolaus & Company

Yeah, thanks for taking the question. Stan and Richard, I guess when I look at the KYNAMRO data it looks like you get about 75% to 80% of your maximal reduction in LDL occurring within the first 12 weeks and there’s still quite a bit of additional benefit beyond 12 weeks and so. Should we be thinking about this in the same context; is that -- are those kinetics that are specific to the lowering of LDL or are they specific to the distribution kinetics of the chemistry within the target issues?

Stanley Crooke

They are tied almost directly to the elimination half life of APOCIIIRx is a little shorter than KYNAMRO but we don’t believe in 13 weeks we have achieved the maximum reduction that would be obtained at steady state. So, the short answer is, you should probably expect behavior that’s similar not equal but similar of what you saw with KYNAMRO. Richard, do you want to amplify on that?

Richard Geary

No, I think that’s exactly right. It looks like we’re getting really robust effects in 13 weeks and when you go beyond 13 weeks to six months I think you can expect with these long half life drugs that you would get even more.

Stephen Willey - Stifel, Nicolaus & Company

Okay. And then can you provide any color around whether or not, I know the changes here were small in terms of the LDL increases, but were they also dose dependant. I think we have just a 300 mg data in terms of LDL?

Stanley Crooke

Not precisely dose dependant, but the challenge here is not a bit statistical, and so we have a difficult time knowing how to interpret the LDL. And what our advisors tell us is to report on non-HDL which is more consistent and more important.

Stephen Willey - Stifel, Nicolaus & Company

Okay.

Richard Geary

And for non-HDL and for apoB there is dose dependants, in the LDL it's too easy.

Stephen Willey - Stifel, Nicolaus & Company

Okay. Thanks.

Stanley Crooke

I think one of the remarkable things that we’ve observed in the patients who come in with the super high triglycerides almost all of them are getting to below 150, and they’re getting to below 150 without any other drug. So, if you have a triglyceride disease, if you have a triglyceride disease, getting your triglyceride as low as possible so that you can eat a normal diet and not worry about it and live a normal life I think will be very important to people.

Operator

The next question is from Jim Birchenough with BMO Capital Markets. Go ahead please.

Jim Birchenough - BMO Capital Markets

Hi guys congrats on the data, I had a few questions, just on getting to below 150 sten what was the highest baseline that was able to get below that level, you know did the 18, 20 patient get below 150?

Stanley Crooke

I can’t remember which patient that is, but of the -- we have now five patients who have competed in the 300 mg cohort all five were 150 or below. And the highest level in that group ratio was what?

Richard Geary

702, that’s down to – below to 150.

Jim Birchenough - BMO Capital Markets

Below 150. And I know you want to save the FCS discussion for September 21st, but maybe when you talk about a global market of 3000 or 5000 patients, how many patients are identified in the U.S. and is there some prospect for you guys retaining rights for the orphan or ultra-orphan indication?

Stanley Crooke

Richard, who don’t you respond to the first and then I’ll take the second.

Richard Geary

Okay. I apologize I heard that last half of the question, I didn’t hear the first.

Jim Birchenough - BMO Capital Markets

Yeah, just in the U.S. what's the number of patients who have been identified with FCS and what – how are they treated currently? Is it apheresis or something else and then for Stan it was really, is this something, is ultra-orphan indication something you can hang on to yourselves?

Richard Geary

Yeah, so first of all the identified numbers in the U.S. are really identified through the lipid centers here in the U.S, these are patients that are sick enough that they’re being treated in specialty centers, so they are known and the estimates are anywhere – are very similar to the HoFH, somewhere in the 1 to 3000 numbers, very low numbers overall. And because these patients have such high triglycerides they are seen in the lipid clinics often because they’re coming into the hospital with pancreatitis often acute pancreatitis on a regular basis. So that’s the situation with and the numbers.

Stanley Crooke

And with regard to current treatment there really isn’t anything but apheresis. You’ll remember that Novartis has a 30 patient Phase 3 study, I think it's 30 patients, Phase 3 study on a drug called DGAT1 that reduces chylomicron absorption, produces diarrhea as a -- I think it's principle side effect. So that gives you a sense of the size of the patient population and the size of the FDA requirements for a Phase 3 program in FCS. And we are as we said with regard to partnering and Lynne can amplify on this. We have already overwhelming interest in this drug as the fellows who’ve been at the ESC kind of test.

But we're not willing to partner today we plan to do a good bit of the Phase 3 obviously somebody comes in and makes a preemptive offer where the dollars look right we’d certainly consider it, but that’s not our plan today. It is not our plan to commercialize the FCS indication ourselves but to make that a part of the package that we license.

You’ll remember that a simple minded view of the rolls of apoC-III on lipid would argue that an APOCIIIRx agent that is an agent that reduces apoC-III would be very unlikely to work in patients with FCS because these are people who have none of the enzymes that apoC-III is thought to prevent from working. Nevertheless there’s been a lot of discussion over the last few years about other things that apoC-III might do, so we decided to go ahead and study in these patients. And as I say, we’ll be reporting those data on September 21st and I’ll withhold further comments on those data of these patients until then Jim. Lynne, do you want to add anything to our partnering or anything?

Lynne Parshall

No, I just would reiterate that the fact that there is a tremendous amount of interest in this drug and I think the data justify that.

Jim Birchenough - BMO Capital Markets

And just a quick final question Stan, with KYNAMRO we saw patients that had the most rapid and profound reductions in LDL being the patients where you might see things like fatty liver; is there anything remarkable about patients that have massive reductions from 720 to less than 150 in terms of anything particular to their side effect profile or it doesn’t look pretty much the same no matter how rapid and profound the reduction is?

Stanley Crooke

I think what's remarkable is there is no safety issue that we’ve identified to date. Remember that the liver side effect’s were tied to a rapid reduction of apoB-100 and it was a -- has been a rapid change in lipid distribution in the liver. So to date we have seen no -- we see elevations that are drug related and so there is no effect. And there certainly is no increase in propensity toward ALT elevations as a function of incoming triglycerides or the rate of extent of reduction of triglycerides to date.

Jim Birchenough - BMO Capital Markets

Thanks, Stan.

Operator

(Operator Instructions) And our next question is from Salveen Richter with Canaccord. Go ahead please.

Andrew Goldsmith - Canaccord Genuity

Hi, this is Andrew Goldsmith on the line for Salveen. Congratulations on the nice data. Just looking between trials to my kind of untrained eye it looks like maybe the monotherapy trial gave slightly better results than the fibrate trial. Is there anything real there or is that just kind of a low ends that work?

Stanley Crooke

Oh my goodness no. I mean to have totally different sets of investigators, trials, patients and end up with a 70% versus 79% reduction is astonishingly consistent. So we look at those data and we can see no evidence that there is any difference as a function of incoming triglyceride whether you’re on fibrates or not, essentially we get the same response in everyone who walks in the door.

Andrew Goldsmith - Canaccord Genuity

Okay, great.

Stanley Crooke

The short answer to your question is those are not – those are numbers that are so close together that it really surprises me to see that level of consistency and if are we doing two single agent study and saw a 79% and 70% reductions and they were two separate studies, I wonder how in the world we got those consistency, so no there’s no difference. Richard, do you want to add anything to that?

Richard Geary

No, that’s exactly right. Consistency is amazing.

Andrew Goldsmith - Canaccord Genuity

And you feel the same way about HDL and the LDL and all the parameters there, they are all basically the same?

Stanley Crooke

Yeah, I think there is obviously dose dependence in the HDL effect just as there is in the apoC-III and triglycerides. But if you look across the board, is there a difference between 40% and 48% and 54%, I can’t imagine it. So if you look at the 300 mg dose which is the Phase 3 dose, I think one of the very comforting things to me as the drug developer is how absolutely consistent the efficacy is and the fact to date they have no non responders.

Andrew Goldsmith - Canaccord Genuity

Great. And then maybe thinking about the kinetics of it, it looks like now the last injection week 13 and you still have kind of maintenance of efficacy about 40 days later, is that returned to the Phase 3 trial or you’re still going to want kind of the weekly dosing?

Stanley Crooke

We’ll do weekly dosing. We think that’s the best with these drugs and it's consistent, remember all these drugs behave very similarly. All of the second generation antisense drugs have elimination half life that were about two to four weeks. So you can just assume that the kinetics of the behavior of response will be very similar. And what that means obviously is that after you stop dosing at 13 weeks you probably should and we always do see a continuing decrease for another week or two because you haven't gotten to steady state there. And after dosing terminates, you have benefited probably, you last for two to three months or longer.

Andrew Goldsmith - Canaccord Genuity

Great. And then maybe just the last question for Dr. Gaudet, the lack of non responders is really quite striking, can you conceptualize any kind of patient population that you might expect to non respond or is this just – it should work in everyone?

Daniel Gaudet

Well at this point as Stan said and as you have seen on the slides presented there were no non responders, over time with additional data on more patient we’ll see (indiscernible) but at this point, it will, obviously triglyceride in heterogeneous population or different diseases, different pathways, different risk associated with high TG. So over time we will see but till now, I’ll tell you that I am quite impressed by the fact that there were no non responders and a huge decrease in TG.

Stanley Crooke

Probably the answer you would have gotten two years ago or a year ago or six months ago which is still a valid answer I suspect is the patients with FCS would be expected not to respond or not to respond nearly as well to APOCIIIRx than other patients. But as I say we’ll show you what we’re getting in those patients on the 21st and then you can make your mind up.

Andrew Goldsmith - Canaccord Genuity

Thanks so much.

Operator

The next question is from Ted Tenthoff with Piper Jaffray. Go ahead please.

Ted Tenthoff - Piper Jaffray & Co.

Great, thank you very much, and congrats on very impressive data. Digging little bit more into the Phase 3 side if I may, you described the injection by reactions as infrequent and mild; can you give us a little bit more color around that?

Stanley Crooke

Well we have done it as well as we can, I think Dr. Gaudet’s quote probably does the best Ted which is that the patients actually get along with the drug very well, and there’s a night and day difference between the injection side reactions with KYNAMRO and APOCIIIRx and as I said repeatedly I think we did the drug at the surplus I think we have exaggerated the injection side reactions with KYNAMRO.

Ted Tenthoff - Piper Jaffray & Co.

What do you think the difference is between…

Stanley Crooke

I can’t add any more than what I have talked about for the last four or five calls, we continue to advance our screening. And as a consequence we're with the same chemistry, same design. We’re getting anywhere from – well we’re just about doubling potency when you look at it roughly. Certainly 70% increase in potency and we imposed a new screen that we think is working and helping us reed out those molecules, those sequences that are a little bit prone to produce overall injection side reactions. But again I want to emphasize that KYNAMRO injection side reactions are absolutely no worse than AMRO, I think what really happened with KYNAMRO is that this was the first subcutaneous drug used by most of the physicians in the trials and we should have spent more time educating them on what to expect from a subcutaneous drug. So yeah, I think apoC-III is performing better in all ways than KYNAMRO in terms of injection side reactions, flu like syndromes and so on and those problems with KYNAMRO were exaggerated.

Ted Tenthoff - Piper Jaffray & Co.

Okay, thanks.

Daniel Gaudet

Well, Stan if I can add something on that, based on what my experience with the [mipomersen] and (indiscernible) right at the beginning before we started the clinical trials I was expecting higher incidents of local reaction due to the fact that patients with high triglyceridemia in general have adipose tissue, which is more (indiscernible). But what’s well served in the field is that the incidents of local injection side was as a matter of fact lower that’s what we have observed with [mipomersen] in our clinical trials. At this moment obviously we're still -- we’re still looking at data on this drug in small number of individuals but we’re certainly not dealing with higher prevalence or incidence of local reactions (indiscernible).

Ted Tenthoff - Piper Jaffray & Co.

Okay. That’s helpful, thanks.

Stanley Crooke

Any other questions please.

Operator

There are no further questions in the queue. So this concludes our question-and-answer session. I would like to turn the conference back over to Dr. Crooke for any closing remarks.

Stanley Crooke

Well, thank you very much everyone. We are tremendously excited about our lipid franchise. We are excited about KYNAMRO and its potential. We think APOCIIIRx is going to be an important drug to reduce triglycerides. We are quite excited about our apoA inhibitor that we’ll be reporting data in November, and behind that other drugs that are coming and we’ll be talking to you about in the near term. We think this lipid franchise that we have created is unique in the industry and of unique potential value. With apoC-III and its follow-on being sort of the at the head of the line today. And as I say, we will report additional data on apoC-III on the 21st and then more data on apoC-III at the AHA and then we’ll introduce you to another member of the lipid disorder family of drugs and that’s our APOARx drug where we’ll report first clinical data on that at the AHA. So we have an exciting fall and winter coming in our cardiovascular and other pipelines and we look forward to sharing with you. Thanks very much.

Operator

The conference is now concluded. Thank you for attending today’s presentation. Please disconnect your lines.

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