Ionis Pharmaceuticals Inc (IONS) 2010 Q4 法說會逐字稿

Good day, ladies and ladies and gentlemen, and welcome to the Isis Pharmaceuticals year-end financial results conference call.

Leading the call today from Isis is Dr.

Stan Crooke, Isis' Chairman and CEO.Dr.

Crooke, please begin.

Good afternoon, and thank you for joining us on today's conference call to discuss our year-end financial results.

Lynne will discuss the financials, and some of the key highlights that contributed to our successes of last year.

After that, I will focus on the year ahead, and focus in particular, on the key goals for 2011.

Joining us on the call are Lynne Parshall, COO and CFO, and Richard Geary, Senior Vice President and Development, Beth Hougen, Vice President of Finance, and Kristina Lemonidis, Director of Corporate Communications.

Kris, will you read our forward-looking language statement, please?

I sure will.

Good afternoon, everyone.

A reminder to everyone that this webcast includes forward-looking statements regarding Isis' business, the financial outlook for Isis, as well as Regulus, and it's joint -- it's jointly-owned subsidiary, and the therapeutic and commercial potential of Isis' technologies and products and development.

Any statement describing Isis' goals, expectations, financial, or other projections, intentions or beliefs is a forward-looking statements, 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, commercializing drugs that are safe and effective for use in human therapeutics, and the endeavor of building a business around such drugs.

Isis' forward-looking statements also involve assumptions, that if never materialized, or proved correct could cause it's 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 Isis and it's 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 on Isis' annual report on Form 10-K for the year ended December 31, 2009, and it's most recent quarterly report on Form 10-Q, which are all on file with the SEC.Copies of these and other documents are available from the Company.

And with that, I will turn the call over to Lynne.

Thanks, Kris.

The purpose of my portion of the call today, is to report our financial performance for 2010, and to describe our guidance for 2011.

2010 was another successful year, with Mipomersen once again the focal point.

Mipomersen will continue to be a key area of focus, as we prepare the initial regulatory filings for marketing approval this year.

We remained financially strong, exceeding our financial guidance for 2010.

We ended the year with a pro forma net operating loss of $36.2 million, which was significantly better than the mid to high $40 million range we projected, and we ended 2010 with almost $475 million in cash, exceeding our cash guidance by nearly $25 million.

Our continued financial strength is a result of our successful business model.

As I've explained before, our revenue consists of several different components, including amortization of upfront fees we receive from our partners, R&D revenue we earn from our collaborative relationships, milestone payments, and sublicensing fees.

In 2010, we have new revenue from all of these sources.

We initiated a new collaborative relationship with GSK, that provides with our first partner in our severe and rare disease franchise.

We began recognizing revenue from amortization of the $35 million up front payment we received from GSK in 2010.

We also earned more than $15 million in milestone payments and sublicensing fees, as our partners advance drugs in our pipeline.

The cash we raise from partnerships supports investments in our pipeline and technology.

Our operating expenses for 2010 were higher than 2009, principally due to increases in costs relating to completing the initial Mipomersen Phase 3 program, and advancing Mipomersen towards it's first regulatory filings for marketing approval.

Our costs also increased, due to maturation and expansion of our pipeline, and the completion of our research to optimize our generation 2.5 chemistry.

For example, in 2010, we added three new drugs to our pipeline, expanding some of our core franchises, including [adding] our first anti-obesity drug, our first drug in our GSK collaboration, and a new drug that could have broad therapeutic benefit in cancer.

We also began clinical development on two drugs, our anti-thrombotic drug, and our triglyceride-lowering drug, and two Phase 2 studies on our most advanced internally developed anti-cancer drug.

The work we've done on our generation 2.5 chemistry should significantly enhance the potency of our drugs, and sets the stage for oral delivery.

This chemistry will begin to be reflected in our drug discovery programs, and we plan to have our first generation 2.5 development candidate this year.

Our financial results also include a $4.7 million gain, related to our jointly-owned subsidiary Regulus.

Last year, sanofi-adventis invested a $10 million in Regulus, in return for approximately 9% ownership.

Sanofi-adventis' investment in Regulus, values Regulus at greater than a $130 million, and was the first external value -- validation of the significant value of our Regulus ownership.

Although our ownership decreased slightly to approximately 46%, we recorded a gain of $4.7 million primarily reflecting the increased valuation of Regulus.

We booked this gain on the line called equity, in net loss of Regulus, on our P&L.

This gain is a tangible example of the value of our satellite Company strategy, where we benefit financially, not only as our satellite Company partners advance their programs, but also as the value of our equity investments in these Companies appreciate.

Our progress in 2010 positions us for a busy 2011, as we continue to add new drugs to our pipeline, and advance the drugs already in development.

In 2011, we expect our revenue to increase by more than $10 million.

As in 2010, a significant portion of our 2011 revenue will include amortization of upfront fees, most of which is the amortization of the upfront fees we received from Genzyme and GSK.

In addition, this year we have opportunities for numerous milestone payments, including milestone payments from our partnership with GSK.

In 2010, we received a $5 million milestone payment from GSK, for the identification of ISIS-GSK1.

We anticipate moving this program into clinical development this year, which could trigger a second milestone payment under the collaboration.

And of course, we have the potential to earn the first regulatory milestone for Mipomersen.

Consistent with Genzyme's plans to file an NDA in the United States this year, we will earn the $25 million milestone payment when the FDA accepts the NDA filing.

Based on our interactions with the FDA, and the progress Genzyme is making with the filing, we have sufficient confidence that this filing will be accepted, that we factored this milestone payment into our projections.

Our 2011 guidance is also affected by an anticipated modest increase in our operating expenses of approximately $15 million.

Of this $15 million, approximately $3 million is associated with preparing to manufacture Mipomersen for commercial launch.

Approximately $2 million is associated with the decline in occupancy and support services, for which Regulus was paying us.

This decline in services is a result of Regulus' move to it's own facility to accommodate it's growth.

Approximately $5 million in costs, about $2 million of which are one-time expenses, are associated with our move to a new R&D building in the middle of the year, as the leases on our current older buildings expire.

Because we would have had to invest a significant amount of cash to renovate and maintain our aging buildings, the modest increase we expect for the rent on our new buildings, will be similar to what our expenses would have been had we stayed in our current facility.

This new facility should minimize our facility's costs, and maximize productivity for years to come.

And finally, approximately $5 million of the increase in expenses represents additional R&D investments in our expanding and maturing pipeline.

Drug development gets more expensive as drugs mature at later stages, but we believe the value of these investments create represents the best way for us to use our money.

Later this year, we anticipate reaching the point where we and Genzyme will share the development costs related to Mipomersen, which should decrease our Mipomersen related expenses.

This decrease in Mipomersen expenses is timed perfectly, as it allows to us continue robust development of the rest of our pipeline, while keeping our R&D spending relatively flat.

Of course, once Mipomersen is launched and reaches profitability, Mipomersen expenses will be paid for out of product sales.

In summary, we have an eventful year ahead, where we're projecting our operating expenses to increase slightly.

We're also projecting an increase in our revenue, which will offset a significant portion of our increased spending.

We're projecting the pro forma net operating loss for 2011 in the low $40 million range, a significant improvement over the guidance we provided at this time last year.

We expect to end 2011, with more than $350 million in cash.

As with last year, we believe our guidance is based on a conservative projection, that does not include any new transactions, so any new transaction we complete could favorably impact our guidance, as our GSK transaction did in 2010.

With that, I will turn the call back over to Stan.

Thanks, Lynne.

2011 will be a transitional year for Isis.

A year in which Mipomersen will move from the clinic, through the regulatory process, and continue on it's path towards commercialization.

A year in which we are looking forward to multiple opportunities to present data from clinical trials on many of the drugs in our pipeline, while expanding the pipeline by adding several new development candidates, and always, as always, we'll continue to advance antisense technology.

Of course, the most exciting and most significant events this year, should be the Mipomersen filings for marketing approval in Europe and the United States.

Genzyme and we, are on track for the EU filing in the first half of the year.

Because the US filing will now be slightly different from the EU filing, it may shift into the second half of 2011.

Both filings are proceeding well.

The Genzyme Isis team is focused and fully engaged in both the US and Europe.

We continue to be pleased with the regulatory progress in Europe, and we have also made significant progress with the FDA.

In our recent discussions, they indicated both, that our filing plan was adequate for homozygous FH, and that the path to our filing for severe heterozygous FH does not require an outcome study.

Let me just take a minute to talk about the fatal conditions that we're planning to treat with Mipomersen.

In recent years, the understanding of the genetics of homozygous FH has evolved.

We now know that there are many different mutations, in a variety of genes, that lead to the clinical presentation of homozygous FH.

So, we know that the genetic diagnosis of homozygous FH, goes way beyond just LDR receptor mutations.

This is, of course, why homozygous FH patients continue to be defined, and diagnosed, and treated clinically, rather than genetically.

If you consider patients with just LDR receptor mutations, there may be about 300 of those patients in the US.

However, the clinically defined, clinically defined homozygous FH patient population in the United States is significantly larger.

I've heard -- I am sure you've heard that some companies like Aegerion think that the number of homozygous FH patients in the United States is more like 3000.

So, what do these patients have in common?

First, most of these patients have already had a cardiovascular event, and virtually all of them, can be expected to die prematurely because of their cardiovascular disease.

They have a fatal disease.

Second, despite being treated with maximally tolerated lipid lowering therapy, they still have LDL cholesterol levels over 300 milligrams per deciliter.

So, what we're talking about is providing a new treatment options to patients with a fatal disease for which current treatments are inadequate.

The other patients we're talking about, or were planning to address initially, are very similar to homozygous FH patients.

These are the severe heterozygous FH patients.

These patients are also presumed to have a genetic basis for their extremely high and uncontrolled LDL cholesterol, but just like the homozygous FH patients, they're diagnosed clinically, not genetically.

Also like the homozygous FH patients, they are extreme -- they are at extreme risk for a cardiovascular event.

The cardiovascular events, simply occur a little later in life.

So, what is the difference between homozygous FH and severe heterozygous FH?

Both groups of patients are at risk of death from their high LDL cholesterol levels.

The only major difference is their age.

Patients with severe heterozygous FH tend to be in their 50's when they die of their cardiovascular disease, and tragically, homozygous FH patients die earlier.

We hope Mipomersen will be the therapeutic alternative, that will help these patients lead longer, healthier lives.

Remember, Mipomersen's effects go well beyond just LDL cholesterol-lowering.

Mipomersen lowers all atherogenic lipids, including Apo B, LDL cholesterol, non-HDL cholesterol, [Lp-a], and triglycerides.

Each of these measures is a recognized, independent cardiovascular risk factor.

Mipomersen does all of this, while not affecting HDL, or good cholesterol, and we can make these assertions with great confidence.

We've completed a robust Phase 3 program, that included four randomized, placebo-controlled trials, in which all patients receive the same 200-milligram per week dose.

In fact, no adju -- dose adjustments of any sort, were allowed in these trials.

All the data we have reported, and that you have seen is based on intent-to-treat analyses, that include every single patient treated in these trials.

We showed consistent, highly statistically, significant results across all four of those Phase 3 trials, in four different patient populations.

Now, compare our Phase 3 program to that of the MTP inhibitor.

The MTP inhibitor being developed by Aegerion has -- it has reported a single, uncontrolled study with 29 patients, individually dose titrated to maximally tolerated dose, while on a very restricted diet to avoid exacerbating the diarrhea caused by the drug.

Clearly, the overall profile of Mipomersen, demonstrates that Mipomersen is a cut above the competition including anything on the horizon, and of course, we have completed a much more thorough Phase 3 program than the MTP inhibitor.

Some of the most exciting progress that has been made recently, is the evolution of Genzyme's plans to commercialize Mipomersen for these initial patient populations.

Genzyme has learned FH patients are under-diagnosed, under-treated, and under-served.

One reason for this, has been that the only treatment option available to these patients has been LDL or pheresis, but there's been little interest in identifying these patients, since there were so little to do for them.

Patients with this disease are best treated by lipid specialists, and one of the keys to Genzyme's strategy is therefore to increase awareness of FH as a fatal disease.

They're planning to launch an initiative to educate healthcare potentials -- professionals to promote early detection of FH, and to assure that these patients are referred to lipid specialists, who are experienced in managing these very sick patients.

So, initially, Genzyme plans to concentrate it's commercialization efforts on getting the patients identified, and referred to lipid specialists, and then providing Mipomersen, and all the tools that assure good patient compliance.

To -- and providing these tools so this small, well defined, very knowledgeable group of physicians.

In fact, another important component of the commercialization plans Genzyme is developing, is to ensure patient compliance.

There we really benefit from all that's been learned by companies like Amgen, and others who have successfully commercialized subcutaneously administered drugs.

It's very clear from their experience, that providing guidance on how to administer the drug, and setting expectations about injection site reactions, are the most important things to do to enhance compliance for any subcutaneous drug.

So, Genzyme is developing these materials, and of course, once they're developed, they should provide important improvements in compliance, and ongoing clinical trials as well.

We believe the Genzyme has the commercial infrastructure, and the aptitude to globally commercialize Mipomersen.

We also believe that Mipomersen will benefit from the added muscle that sanofi-adventis will provide.

Before I move beyond Mipomersen, I do want to remind you that this year, we'll be reporting detailed data, from the final two of the initial Phase 3 Mipomersen studies.

These studies were conducted in patients with severe high cholesterol, and in patients with high cholesterol, high cardiovascular risk.

These data will be presented at the AECC in early April.

Remember, that we've reported top line data from these studies, but at the AECC, we'll have the opportunity to provide more detail.

As we've done in the past, we plan to host a physician panel that will be webcast to discuss these data.

So, we have an exciting year ahead for Mipomersen.

However, with 24 drugs in our pipeline, we have many other events to look forward to as well.

For example, just last week, we announced that our CRP inhibitor, reduced CRP in normal volunteers.

It's the first time a selective CRP inhibitor has been shown to work in man.

We plan to launch a Phase 2 program to evaluate the benefits of lowering CRP, in a number of diseases like multiple myeloma and rheumatoid arthritis.

Our partner, Excaliard, has reported top line data from three, very positive Phase 2 studies, with EXC 001 showing dramatic improvements in scarring.

They'll be reporting detailed data from these studies, and initiating additional trials.

Our SGT -- SGLT-2 inhibitor, a drug designed to treat diabetes by increasing the clearance of glucose in the urine, is completing it's initial trial, and we plan to report the data from that this year.

We plan to report results from our initial trial on our ApoCIII inhibitor, a selective triglyceride lowering drug, this year as well.

Similarly, we plan to report data from our initial clinical trial evaluating our new drug, a Factor [XI] inhibitor to prevent unwanted blood clots, and progress is continuing on our more advanced anti-cancer drugs, such as OncoGenex's drug, OGX-011 and OGX-427, Lilly's survivin inhibitor, and our drug in Phase 2 development, the eIF-4E.

Additionally, we expect to initiate clinical trials in several more drugs this year.

We continue to advance antisense technology, and take advantage of the ever-expanding knowledge of the RNA world, as well.

We announced in January, that we're ready to take the next step in antisense technology, the implementation of generation 2.5 chemistry.

We believe the generation 2.5 drugs will be five to ten times more potent than drugs currently in development.

If you think about the dose of Mipomersen, it is about 200 milligrams a week, that would mean a dose of 20 to 40 milligrams a week, for a comparable generation 2.5 drug.

Lower doses mean fewer side effects, far less concern about injection site reactions as well, and a lower dose makes oral dosing of antisense drugs commercially feasible.

Cost of therapy should also be reduced, because we'll be giving less drug.

These are obviously advances that'll make our drugs better, and expand our market opportunities.

This year, we plan to move our first generation 2.5 antisense drug into development.

I am sure you'll remember that last year, we hosted a series of pipeline calls, and we've gotten quite a bit of positive feedback about those calls.

So, this year, we are continuing our efforts to share with you the tat, strat -- strategic and tactical rationale for the drugs in our pipeline, and as they have news, or reach important development milestones.

Our goal is to highlight just a few drugs, in each one of these calls.

Our next pipeline call is scheduled for April, so we hope that you'll be able to join us for that, and, of course, we'll be sending out all the call details, as we get a little closer to the date.

So in short, 2011 is going to be an important year.

Mipomersen is front and center.Making Mipomersen a commercial success will continue to be our primary focus this year.

But in addition, the rest of our pipeline and technology will continue to advance toward many important milestones, and we're going to be doing this, with a minimal increase in R&D spending, and an NOL forecast that's in the same range as our 2010 forecast.

So, with that, I want to thank all of you for joining us today, and we'll open it up for questions.

Derrick, if you can set us up for questions, we'd appreciate it.

(Operator Instructions).

Our first question comes from the line Eun Yang from Jefferies.

You may proceed.

Thanks very much.

A question to you, Lynne.

I heard you in your prepared remarks, that the $25 million milestone that you guys are expecting from Genzyme, is upon the NDA acceptance by the FDA.

But my understanding, was that the first of $25 million milestone is upon regulatory filing, whichever comes to first, between US and EU?

Can you clarify that?

So the first milestone is a US milestone, and it is for the acceptance of the filing, which typically happens 30 to 60 days after the NDA is filed.

And then is there --

It is not approval.

But is there a milestone for [EU] filing?

No, it is for the US filing.

Okay.

And then, the second addition or $25 million, is that the approval upon --

Yes.

-- US approval or EU approval?

It is for US approval.

I see.

Okay.

And the second question, is any update on the study that required a (inaudible) of your heterozygous FH patient in the US, in terms of the design?

We're still working out the details of that with the FDA.

Until we finished working out the details, we're not going to provide a lot of detail about that.

Okay.

Thank you.

Your next question comes from the line of Mark Monane from Needham & Company.

Please proceed.

Thank you very much for the comprehensive review.

I have a couple questions.

First for Lynne, does your figure at the end of the year for the cash position of Isis, does that count any collaborations that you may form, or does it count the milestone payments that you just went over?

How did you get to that number?

So, Mark, it does not -- as I said, our projections, as they always are, are conservative.

And don't assume any new transactions, But our projections do include the milestone from Genzyme, for the first milestone, the $25 million milestone that I mentioned.

Great.

And then I heard Stan say, tell me if I am right, Stan, that mipomersen commercial success is the priority for 2011?

Did you talk about any more trials that are being done by Isis or Genzyme, on either different doses?

Or perhaps the trial that I think that you were talking about in January, potentially to get a broader label?

No.

We didn't discuss it, although Lynne answered the question for Eun Yang.

As you know, we are pursuing alternative dose schedules, daily dose, three times a week, and weekly dosing.

And we will continue to work on that.

And the goal there, long-term is to provide patients the choice of how they want to give themselves the drug.

And as Lynne mentioned in her answer to earlier, we are in well along in the process of designing the additional trial for severe, and we won't be discussing the details of that, until we are confident that we have a solid agreement with the FDA.

Got it.

And then, the -- a final question, Stan, I thought I heard you say that one of the advantages of the antisense technology was to target un-druggable targets.

And that there was a plan to go forward, targeting different targets that weren't available, or weren't being attempted by other people.

I guess the question for me is, does it matter in your opinion from what you know, and from I guess what Richard knows, how the CRP level is reduced, maybe it is reduced by lipitor?

Or maybe it is reduced by the antisense compound?

Does it matter how the PCSK9 target is reduced, if by an antibody or antisense?

Do you have a point of view there?

Well, with CRP, I think what matters with CRP is, as I understand it sort of the maximum reduction in CRP, that a statin will generate, is anywhere from 15% to 30%.

And we would like to think, and we'll have to wait until we generate all the data in Phase 2, but we would expect to be able to provide doses that reduce CRP, by virtually any level we want.

I think most people who think about CRP, would like to see their patients below 1.

And it is a very rare patient who has really elevated CRP achieves that target with a statin.

So I look at CRP, and I say our strategy there, is really quite the same as with most of our drugs.

Our drug would be used in combination with other drugs, to achieve targets that are unachievable with existing agents.

With regard to PCSK9, there are lots of theoretical reasons why reduction of PCSK9 through antisense mechanism might be more attractive, than through a monoclonal antibody.

But I think it remains to be determined, which method appears to be the most attractive, as you generate the clinical data that define the profile.

Thanks very much for the added information.

Your next question comes from the line of Eric Schmidt from Cowen and Company.

You may proceed.

Good afternoon, and thanks for taking my questions.

Lynne, I just wanted to make sure I heard the finer points of your 2011 guidance correctly.

Did you say that total revenues would increase by more than $10 million year-on-year, and OpEx by 10 to 15?

What I said was revenues by 10, and expenses by approximately 15.

Thank you.

When is it appropriate for you to have direct conversations with sanofi?

I assume that you couldn't of have had any, yet?

As you know, we have ongoing interactions with sanofi through our partnership through Regulus.

If you are referring to specific interactions around mipomersen, I would rather just not answer that question.

And just say that we're working with our colleagues at Genzyme, and eventually with sanofi to be sure that mipomersen gets everything that it needs.

Let me ask it a different way, Stan.

Do you have any sense either from Genzyme, or other avenues that sanofi is not committed to mipomersen?

No, quite the contrary.

Thanks.

And the last question is about Regulus, and the ownership structure.

I am wondering whether there comes a point in time when you, or they can out grow the current ownership, and it makes sense to look at different structures?

Well, we expect Regulus to be successful.

And what that would mean eventually is, that it would become a public company.

And you'd maintain your ownership and your share of their losses at that point in time?

Obviously, there would be some dilution, but you have no interest in otherwise monetizing that?

I think we're committed to Regulus being successful, in advancing the use of antisense drugs to reduce microRNAs, and What we're -- I think we're very pleased with the start that Regulus has.

We're no longer putting money in.

We're taking money out, which is well ahead of where we thought we might be.

And obviously, as it matures, we'll continue to look at the progress it makes, and opportunities to monetize in a variety of ways, and make decisions that we think are appropriate for shareholders.

Last question about the EME -- the EMEA -- and when will you, with the filing approaching now in the first half of this year, when will you know, whether you will be able to file for the severe heterozygous FH population?

Lynne will answer that.

Well, based on the interactions we've had so far, we have a very high level of confidence, that we will be able to file for that in Europe.

Okay.

So, Lynne, is the next update for us, just you file for HEFH.

And if we don't hear anything, we're assuming you're on track?

Yes.

Thanks.

Well, not HE --.

For severe, I am sorry.

Yes, thanks for correcting that, Stan.

Yes, it's important, because we do plan HEFH filing in Europe at some point.

Yes.

Absolutely.

My fault.

Very good.

Yes, yesSo, Eric, I think we're feeling very optimistic.

Okay.

Thank you.

Your next question is from the line of Shiv Kapoor from Morgan Joseph.

Please proceed.

Thanks for taking my questions.

And congratulations on the recently reported data on the CRP drug.

My question is, what kind of Phase 2 are you planning on running?

Will you be running two studies to start with, one in multiple myeloma, and the other in RA?

And what are you looking for in your Phase 2 studies?

What will be the end points?

Richard, would you like to deal with that?

Sure.

I'd be happy to.

So initially, and for this year we're planning to move into two Phase 2 programs.

One in rheumatoid arthritis, in which the end points will be, of course, CRP, but also symptomatology in the disease.

And the second, is in multiple myeloma, what we'll -- which we'll be looking at only the reduction of CRP, but also symptomatology and chemosensitivization.

So those are the end points, and the studies that we have planned for this year.

And I think did -- I answer all of your questions?

What kind of end points will you be looking at?

And what kind of results would you expect?

So, and the rheumatoid arthritis, would be the typical scoring, the --

ECR?

Yes.

And in the multiple myeloma, I think we're doing two things.

We're going to be pre-treating people who have apheresis, because of high levels of Bence Jones proteins, and so on, And there are those people, who undergoing pheresis, end up with a pretty heavy cytokine storms, and lots of symptoms, and we'll see about trying to make that better.

And then, we'll be looking at response rates, and the usual things in the -- in the trial that looks at just on going treatment of multiple myeloma.

I think that's right, isn't it, Richard?

That's correct.

Okay.

Thanks a lot.

Okay.

You bet.

Your next question is from the line of Carol Werther from Summer Street.

You may proceed.

Thanks for taking my question.

At the time of the filing in the US, can you just give us an idea how large the package is, and how many patients you have out on the [placebo-controlled], since, say one year.

Sure.

Richard can probably give you a little more accurate numbers than I.

Okay.

So far one year, the number is 107.

And that is for the twelve-month greater than or equal to one year.

And the total number of patients that are subjects that we treated is about 700, Richard?

Yes, it's over 700.

It is about 733, something like that.

And that includes -- that's -- every trial we did I think every trial we did was placebo-controlled.

So all four Phase 3 trials, of course, were placebo-controlled, and meet the well-controlled definition.

And our Phase 2 trials were as well, Carol, as you remember.

Okay.

Right.And then what kind of monitoring, do you anticipate to be on the label for liver safety?

Lynne, do you want to deal with that?

Of course, we're not going to know that, Carol, until we get to that point with the agency.

And so anything that we would say is conjecture, but we do expect as with all lipid-lowering drugs, that there would be monitoring of ALT elevations, probably more frequently in the beginning, and less frequently over time.

That is exactly what we have done with the statins, and we would expect something similar.

Thank you.

(Operator Instructions).

Our next question comes from the line of Charles Polsky from William Harris Investors.

Please proceed.

Hi, guys.

When I think of CRP roughly, I think of it as a marker of inflammation, and given the study reduced CRP levels, I am just curious, if in other drugs, particularly mipomersen, there were patient who is saw injection site reactions?

Was there any reduction in injection site reactions, in a CRP lowering drug versus a mipomersen?

Was it less of an issue?

No.

So the first point is that mipomersen itself causes no long-term increase in CRP.

And secondly, we have evaluated mipomersen extensively, in terms of just it's pro-inflammatory potential.

And we're reporting those data, and we're very encouraged by what we have seen.

Okay, but my question was, so if you have a CRP lowering drug, --

I am getting to that.

Okay.

So, so, in the study that we had, only the highest dose cohort had elevated CRP.

And so, I think we really can't comment on whether it's ISRs, injection site reactions, or less or more.

We certainly didn't see much, in the way of injection site reactions, but we don't believe injection site reactions are associated with -- or secondary to CRP releases.

Richard, you may -- so it is a question that is thoughtful, and one that we asked some time ago.

And we no longer think of injection site reactions, as having much to do with CRP.

Richard, do you want to amplify on that?

That's exactly right.

We actually will be reporting data, both at the ACC, and then additionally the Phase I study where we looked at multiple markers, and there is no association between ISRs and CRP.

So --?

It was exactly the question we had been asking for the last few years.

And it turns out they're -- they seem to be entirely unrelated phenomena.

Okay.

Thank you.

You bet.

At this time, I am showing no further questions in queue.

I would like to turn the call back over to Dr.

Crooke for any closing remarks.

If there are no further questions, I want to thank you again, for your attention.

And just to recapitulate, we look forward to 2011.

And our primary focus in 2011 is to ensure that mipomersen is -- the files are appropriate, and we move towards commercial success with mipomersen.

We're encouraged by what we're -- by the progress being made, both in the US and Europe.

And we're very encouraged by the progress that Genzyme is making, in getting ready to commercialize mipomersen.

We also look forward to significant news events from our pipeline, that will sort of dot the landscape throughout the year.

Thanks very much.

Ladies and gentlemen, that concludes today's conference.

We thank you for your participation.

You may now disconnect.

Have a great day.