Ionis Pharmaceuticals Inc (IONS) 2008 Q4 法說會逐字稿

Welcome to Isis Pharmaceuticals year end financial results conference call.

Today's call is being recorded.

Leading the call today, from Isis, is Dr.

Stan Crooke, Isis Chairman and CEO.

Dr.

Crooke, please go ahead.

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

Joining us on today's call are Lynne Parshall, COO and CFO; Beth Hougen, Vice President of Finance; and Kristina Lemonidis, Director of Corporate Communications.

Chris, will you read our forward-looking statements, please?

Sure, thanks, Stan.

Good morning.

A reminder to everyone, this Webcast includes forward-looking statements regarding Isis' business, the financial outlook for Isis, as well as Regulus its majority-owned subsidiary and the therapeutic and commercial potential of Isis' technology and products and development.

Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' goals.

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 products.

Isis' forward-looking statement also involves assumptions that if, never materialize or proved correct, could result -- 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, 2007 and its most recent quarterly report on Form 10-Q, which are available on file with the SEC.

Copies of these and other documents are available from the Company.

Stan, back to you.

Thanks, Kris.

The first The purpose of the call today is to report our financial performance for 2008 and to define our agenda for 2009.

We had a great year in 2008.

We continued to add corporate partners with the deal with Genzyme for mipomersen.

We completed the sale of our diagnostics subsidiary Ibis to Abbott Molecular.

From these and other transactions, we have generated more than $650 million in new cash over the last 24 months.

And of course in 2008, we continued to make progress in our pipeline.

Moving mipomersen into broad Phase 3 programs to support our first planned NDA in 2010, with a planned launch in 2011.

We reported positive data for several drugs in key clinical trials and made progress on all of the drugs in our pipeline.

In addition, we put two new drugs into development.

A unique aspect of our business is our satellite company strategy.

And the value of that strategy became even more apparent last year, as our partner companies continued to mature.

Most importantly, they presented positive clinical data from studies on our drugs that we have partnered with them, including the results of OGX-011 trials in patients with prostate cancer and a very exciting Phase 2 study evaluating ATL TV-1102 in patients with multiple sclerosis.

Further, our satellite companies achieved important new partnerships.

Our partners at ATL completed a partnership with TEVA.

Regulus completed its first partnership with GSK.

And our partners at Alnylam continue to achieve new partnerships from which we at Isis benefit.

And of course the sale of Ibis, our first satellite company to Abbott was one of the highlights of the year.

As a result of these activities, we have significantly strengthened our financial position.

We start this year with more than $650 million in cash.

We are pleased that we are in the relatively small group of successful and well-funded biotech companies that do not need to raise cash in these difficult economic times.

Now, Lynn, perhaps you can go over the financial details.

Thanks, Stan.

As usual, I will assume that you've read the details of the year and quarter end financials in our press release this morning.

2008 was a transformational year for us, with multiple successes in all aspects of our business, resulting in the strongest financial position in our history.

Let me start by going over the highlights of our 2008 financial results.

First, we exceeded our 2008 guidance of pro forma NOL of less than $15 million, ending 2008 with a pro forma net income of $3.1 million and net operating income of $226,000.

Second, we ended 2008 with nearly $500 million in cash.

This is more than the $450 million we projected and does not include the $175 million that we received in January from the sale of Ibis.

The considerable improvement in our financial results was driven primarily by significantly increased revenue from partnerships.

In addition to creating a significant continuing revenue base, our partnerships have greatly improved our cash position.

We've been cash flow positive for the last three years and we expect to be cash flow positive in 2009 also.

Our projections for 2009 are for a pro forma net income of more than $140 million.

We expect to end 2009 with more than $550 million in cash.

And we project a pro forma NOL in the low to mid $20 million range, which is slightly higher than our 2008 NOL would have been with Ibis included.

The accounting treatment for the sale of Ibis to Abbott is somewhat complicated.

So I'll spend just a few minutes walking you through the impact on our 2008 and 2009 financial statements.

First and most importantly, the sale of Ibis added $175 million to our cash, bringing the total to over $650 million at the beginning of the year.

In addition, we expect continued financial benefit as a result of this transaction because we receive an earnout that starts at 5% on Ibis future sales on the terms we've previously described.

We will record a gain on the sale of Ibis in the first quarter of 2009 of approximately $200 million.

You will see this on our P&L below our operating results on a line called discontinued operations.

This gain is a significant contributor to our projected net income for 2009.

Because Abbott exercised this option in 2008, Ibis is considered an entity held for sale for the entire year of 2008.

Therefore, we no longer include Ibis revenue or expenses in our operating results.

In other words, in the 2008 financial results that we reported today, our operating results do not include Ibis financial results.

Ibis' results are instead included on the line called net loss from discontinued operations.

The good news is that Abbott and Genzyme transactions contributed to very strong financial performance in 2008 and will also in 2009.

The flip side is, that for the first time in our history, we will have taxable income.

To minimize our federal tax liability, we will use our NOL carry-forward to offset a majority of our taxable income.

However, due to the recent California tax law changes that were enacted with the 2008/2009 California budget, we are unable to use our NOL carry-forward to offset taxable income for California.

As a result, we expect to owe state tax and possibly some federal tax.

But there are a number of unknowns still, including the recently approved federal stimulus package, which means we don't know, right now, exactly what that number will be.

Because our financial performance over the last several years has been so strong, many of you have asked us to provide additional color on our financial drivers going forward.

So, I'll do that now.

I'll start with revenue.

Most of our revenue comes from licensing and partnerships and our revenue consists of three primary components.

The first component is revenue from the amortization of upfront fees we received from our partners.

For example, we're amortizing $275 million of the upfront payments we received from Genzyme from the license fee and premium on its stock purchase into revenue over four years, through 2012.

We're also recording revenue from the upfront fees we received from BMS and Ortho-McNeil and that Regulus received from GSK.

The second component is revenue we earned for the research and development we performed for our partners and from ongoing licensing agreements.

Typically, when we enter into a collaboration agreement, we conduct research and development activities for our partners for some time, which are partner funds.

For example, we have ongoing R&D efforts related to our BMS and Ortho-McNeil collaborations.

These first two components of revenue are relatively predictable and relatively consistent quarter to quarter and establish a strong base for our 2009 revenue.

You can estimate this revenue base pretty accurately by annualizing our Q4 2008 revenue.

Doing that, the annualized revenue amount is approximately $120 million.

Although less predictable, the third component of our revenue provides meaningful upside to our base revenue.

This component includes milestone payments, sublicensing fees, money from transactions like contract manufacturing, and money from new collaborations.

In 2008, we received over $11 million from these sources.

Already this year, we've received $1 million from Alnylam, resulting from their Cubist transaction and $1 million from Achaogen when they filed an IND for ACHN-490.

While we do not project the exact amount of revenue that we expect to come from this category, it has historically been a significant component of our revenue and we expect it to continue to be so in 2009.

We believe it is likely that we will receive additional milestone and sublicensing revenue this year.

We also think it is likely that we will complete new corporate partner transactions this year.

Obviously, we're in a very different position today than in the past, so we're much more selective in the partnerships we're willing to engage in.

But given the level of interest, we think other new deals may be completed.

Now, let's move on to expenses.

We expect operating expenses to be slightly higher in 2009 than in 2008, principally due to growth in the mipomersen clinical program and in Regulus.

Mipomersen matured appreciably during 2008.

We and Genzyme are currently evaluating mipomersen in four Phase 3 trials.

The ongoing mipomersen study significantly increased the number of patients exposed to the drug in support of future regulatory filings.

Obviously, this expanded clinical effort will affect our expenses.

Regulus will also continue to advance its microRNA technology.

Regulus is in the process of building its core team, augmenting the strengths of the team already assembled.

We expect Regulus to approximately double in size in 2009 from 2008.

We also expect modest expense growth in our other clinical programs, as we advance drugs into and through development.

While we've initiated a new cancer program in research, due to the efficiency of our antisense drug discovery platform, that new program will represent only modest expense growth, while contributing to the three to five new drugs we plan to add to our pipeline this year.

And how does all of this translate to the bottom line?

Over the last couple of years, on a pro forma basis, we've reported three quarters of net income and three quarters of net operating income.

Ending 2008 with both pro forma net operating income and pro forma net income for the year.

Right now we're flirting with sustainable profitability.

We're not there yet but it won't take much.

A new deal, a mipomersen launch in 2011, a major milestone; any of these things could be sufficient to tip us into profitability for the next several years or in the case of mipomersen launch, into the future.

We expect to end the year with more than $550 million in cash and we do not expect to seek additional financing.

So, we're looking forward to another productive year in [2008.] With that, I'll turn the call back to Stan to highlight what you might look forward to.

Thanks, Lynn.

As Lynn said, we've had an excellent year with progress in every element of our business.

I'll close now with a few comments focused on upcoming events in 2009.

So far this year, we've already accomplished quite a few things.

We completed the transaction with Abbott for the acquisition of Ibis.

We've already advanced one of our pipeline drugs into Phase 1 clinical trials.

Our SGLT2 inhibitor went in demand earlier this month and we expect other drugs to follow that this year.

Furthermore, our satellite companies have started the year well.

Achaogen initiated a Phase I trial on ACHN-490, their next generation aminoglycoside, a neoglycoside designed to treat multidrug resistant Gram-negative bacterial infections.

This drug derived from a technology that we created to identify small molecules defined to structured RNA and then we licensed that technology to Achaogen.

So Achaogen added another drug to our pipeline and we earned a $1 million milestone.

We also earned a $1 million sublicensing fee from Alnylam recently announced deal with Cubist.

Here are some of our upcoming highlights.

We plan to report data from a Phase 3 study evaluating mipomersen and homozygous FH patients in the middle of the year.

We also expect to report data from additional mipomersen studies in other patient populations late this year and early next year.

We plan to report data from a Phase 2 study evaluating Isis 113715, our novel insulin sensitizer, [in combination] with sulfonylureas in patients with Type II diabetes in the first half of this year.

We expect to complete Phase I studies for our SGLT2 and our CRP drugs this year.

And of course, completing the Phase I study sets both of these drugs up for Phase 2 studies.

We expect news from our partners as well.

For example, our partners at Altair, who plan to announce data from their Phase I studies with AIR465, an inhaled antisense drug to treat asthma.

Remember that this is the first aerosol drug that we've taken in demand and so that will be important information and take a step toward expanding our opportunities through that route of administration.

We plan to begin clinical trials on three to five new drugs this year and we will add three to five new drugs into development this year as well.

So, we've got a significant agenda.

To add three to five new drugs to the pipeline each year is an impressive but perhaps equally exciting is the breadth and the diversity of diseases we'll be treating.

Our cardiovascular program is now approaching new targets in the management of lipid disorders.

In addition to mipomersen and our PCSK9 inhibitor, we're focused on targets that alter other lipids, such as triglycerides.

Beyond lipid management, our cardiovascular program should add a Factor XI inhibitor that affects the clotting cascade to development this year.

And as I mentioned, our CRP inhibitor will be completing Phase 1 trials.

Our Phase 2 program for our CRP inhibitor will include not only cardiovascular disorders but other inflammatory disorders.

Similarly, our metabolic program is moving beyond Type II diabetes to the identification of peripherally acting anti-obesity agents.

Our new CNS program has already created one development candidate SOD1 inhibitor to treat patients with ALS.

We plan for that drug to enter clinical trials this year and we're looking forward to adding new drugs to treat severe neurodegenerative diseases out of that program in the near term.

We also expect to add drugs from our cancer program.

When you consider these drugs, plus the drugs we already have in development, you can see that we have drugs to treat many types of diseases.

These drugs are delivered by several routes of administration, including aerosol.

And we are focused on indications that range from the very severe and acute to diseases as chronic as Type II diabetes and high cholesterol.

Additionally, as always, we continue to advance our technology.

We're making great progress in learning how to exploit antisense mechanisms other than [RNAH,] such as alternative splicing.

And hope to have a development candidate from our alternative splicing effort this year or next.

Now, this is particularly important because with this mechanism, we cause a new protein to be made.

In effect, we create an agonist instead of an inhibitor.

We're also moving along toward our goal of creating single-strand antisense drugs that cause RNA target reduction via the siRNA mechanism.

We think this could be a breakthrough that the siRNA field really needs.

Finally this year, or early next year, we hope to introduce generation 2.5 antisense drugs.

Our new proprietary generation 2.5 chemistry should increase potency by 10-fold or more compared to the already very potent generation 2.2 drugs that are in the clinic.

So, we'll continue to expand the opportunities for antisense technology and enhance the performance of the drugs in our pipeline in a prudent stepwise fashion that enhances the value of the entire platform and extends our proprietary control much further into the future.

We exceeded the financial and performance guidance that we provided for 2008 and I think that guidance was pretty aggressive to begin with.

In 2009, we'll be cash flow positive and profitable and we'll strive to sustain that as we approach the commercialization in mipomersen.

In summary, this has been another great year for Isis, a year with impressive results in every aspect of our business.

And we expect 2009 to be as exciting as 2008 was.

And with that, I'll now open the phone call up for questions.

Connie, if you can set us up for questions, please?

Thank you.

(Operator Instructions) And we'll take our first question from Joseph Schwartz from Leerink Swann.

Great good morning.

Thanks for taking the question.

I was wondering if you can give us an update on the severe high cholesterol study?

How is site activation and screening going?

And have you started to enroll patients?

Yes, it's going very well.

As we don't provide detailed information on enrollment.

But all of the trials with mipomersen are going well and enrolling.

So I think I heard you say that late this year or early next year, you expect to report or publish some data in other high cholesterol populations.

Would this include this -- I'm sorry, what was called the apheresis-eligible study and can you just explain to us, is that just a nuance with the name change or has the strategy with those patients changed?

Can you take people off of apheresis?

Give us some color there, so we can understand that.

Thanks.

There hasn't been any change in the basic design or the thrust of that trial, Joe.

It's, so -- the right answer is, it's just a name change.

And I think we've said on the last call or two that, we had these four Phase 3 trials that we wanted to get up and running and they're getting up and running and they're enrolling nicely.

And we expect over the -- from the middle of this year to 2010, and I don't want to be a lot more specific than that, to have sort of a rolling series of clinical trials that we'll complete and we'll have those results, all geared toward having the data that we want to use to support our first filing.

So without being more specific about exactly what trial we'll finish, at exactly what date, I think we're feeling very good about where that program stands and that we're going to meet that guidance right on the numbers.

Thanks.

And we'll take our next question from Mark Monane from Needham.

Good morning, and greetings from New York City.

Couple questions, please.

Thanks for the review for starting us off.

When we look at the Phase 3 data, I know they haven't come out.

What kind of result do you think would be clinically relevant, beyond statistically significant, in these patients to make a difference in the real world?

Well, at least the way I think of it, Mark, is that the approval of lipid lowering agents has traditionally been a 15% reduction in LDL.

And these homozygous FH patients, obviously, are on high doses of all the lipid lowering agents.

And so to achieve a 15%, 20% reduction in LDL would be very meaningful event in their lives.

Clearly, in past Phase 2 trials, mipomersen at 200 milligrams per week has delivered significantly greater reductions than that.

All right.

That was helpful.

Now, we saw some data on mipomersen that showed extremely long half life of the drug.

I know that in the current Phase 3 trials, there's weekly dosing.

Are some of the new trials that you're planning thinking about extending the dosing frequency in these patients?

No, not yet.

Our strategy there has not changed.

And that is that we want to do one thing well, which is develop the weekly dosing schedule, have a weekly dosing schedule that's simple and easy to use.

Get that to the market, with as much safety data on that schedule as we can possibly do.

Once we get that done, then we can start looking at other schedules.

There are pluses and minuses to going to biweekly.

There are pluses and minuses to going monthly.

And those things we'll evaluate over time.

The way I think of those things are just great opportunities for line extensions and lifecycle management.

Fair enough.

Concrete question, the three trials that will start this year, Factor XI trial, the metabolic trial, looking at peripheral diabetes, and the SOD trial in ALS, is that correct?

So we have the CRP trial that's underway.

Right.

The SGLT2 trial that's underway.

And we hope to get the SOD1 clinical trials underway.

The Factor XI is a drug that will enter development and won't enter clinical trials until next year.

I'm sorry.

And the peripheral diabetes -- excuse me, obesity management drug?

We expect the drug to go into development this year but it won't get into clinical trials this year.

And then finally, you've given us a lot of therapeutic options in terms of addressing a target.

There's antisense, there's siRNA and with your alliance with your Alnylam.

There's the Regulus microRNA.

And then you talked today about the single stranded sIRNA possibilities.

How is the Company thinking about the technology and marrying them to the different diseases that you're talking about and different trials you're going to initiate?

How do you know which one to use for which?

Well, let's deal with microRNA's first.

MicroRNA's are new targets.

What's happening in our world is, our world in terms of the science is, exploding and new types of RNA's that have important regulatory roles in the cell are being identified as a pace that's dizzying.

MicroRNA's represents one class.

So our thoughts about MicroRNA's have not changed one iota.

That is, they're new targets and we use antisense just like we use for messenger RNA's to effect microRNA's.

So, they're just new targets.

The specific design of the antisense drug may be slightly different from microRNA but it's an antisense drug.

With regard total rest of antisense mechanisms, throughout our history, we have studied all of the major mechanisms.

Those are things -- what happens to the RNA after the drug binds.

The mechanism that has proven to be the most productive is RNase H but we have been interested in other mechanisms, like translation arrest and splicing for a long time.

We are very, very interested in alternative splicing because alternative splicing is responsible for a large part of cellular diversity and we think it's accountable for a lot of different diseases.

So that mechanism, we use when there's a disease that we think can be improved by driving the production of a different protein.

And so that's alternative splicing.

siRNA is an antisense mechanism.

The sense strand involved in a double-strand RNA simply is a drug delivery device.

The active molecule is an antisense agent.

And so, our focus in siRNA was to enable our partner, Alnylam, to approach traditional double-strand RNA, siRNA.

And we have been looking at single-strand molecules that work through that risk mechanism.

And the reason we're doing that is that we want to continue to evaluate new approaches that may change and improve some of the properties of our drugs long-term.

With that mechanism, I think we have a long way to go before we know if it provides benefit relative to RNase H.

So think of that as a long-term approach, designed to continue to advance the technology that we've invented.

I'm afraid that was more complicated than it needed to be but I hope that answered the question, Mark.

Did I put him to sleep?

Did I answer your question, Mark?

And we'll take our next question from Brent Kelly from Collins Stewart.

Hi, good morning.

Stan, can you comment on the regulatory strategy for mipomersen?

Homozygous seems pretty straightforward but how are your conversations going with the FDA in Europe with regards to using LDL surrogate end points for indications beyond homozygous?

Brent, I don't have anything to add to the comments that we have made previously.

We've had good productive conversations that give us significant encouragement that the initial indication in Europe that we can achieve with LDL reduction will be broader than simply severe patients.

But I don't think I can go into more detail than that and my preference is to wait until we and Genzyme discuss that in more detail.

Suffice it to say, we're working hard at it and we feel very good about what -- where we are.

Now, is this something that we would learn in '09 in terms of Europe?

We're working at it.

And I don't -- we expect to, yes.

Okay.

But Genzyme is driving this and so I don't want to speak to this.

It's Genzyme's work and Genzyme should be speaking directly to this.

Okay, thank you.

(Operator Instructions) And we'll go next to Eric Schmidt from Cowen and Company

Good morning.

Stan or Lynne, the press release mentions your greater confidence in mipomersen's safety profile with the added clinical experience.

Can you just kind of provide us with an update on the rough numbers of patients who have now been exposed to the drug, three, six or say 12 months?

Whatever metric you want to use?

Well, Eric, I don't want to -- because the numbers change every day, obviously.

The longest exposure that we have with the drug is about two years now.

And I think the total number of patients is approaching 500, 600, somewhere in that range.

And all of the current studies have a dosing schedule of 26 weeks and the opportunity to roll over into an open label or extension study of one sort or another.

So, we are certainly getting a lot more experience, longer than 13 weeks as we speak, with a lot of patients.

And any ref number of patients who may have completed 26 weeks?

I don't have that and I'd be uncomfortable giving it, Eric, because tomorrow it will be different.

Okay.

But if you just think about the fact that CS17 continues, which is the long-term open label extension; and that CS5, which is the homozygous FH trial, has completed enrollment quite sometime ago; and the other trials are enrolling at a very rapid clip; you can see that we're adding people treated for longer than 13 weeks at a very fast pace.

Okay.

That's helpful.

Thanks.

On the outcome study, that I think Genzyme has now indicated will start next year, can you provide us with any rough details on the size and scope of that trial, size and timelines?

Our thinking, about the total numbers and so on, has not changed dramatically.

And so we still subscribe to the view that it will be somewhere in the 5,000 or thereabouts patient range, maybe to 8,000.

And the discussions that we're having relate to; Do we use more patients, shorter time or fewer patients longer time?

And all of these things and they are still in discussion.

So, these are really complicated studies to do, especially with a subcutaneous drug.

And we're spending a lot of time planning.

And I know it seems like a long time to plan but getting this right is much more important than getting it started at a particular moment.

So I'd just ask you to bear with us.

There's just a ton of planning going on to design that trial properly.

Okay.

And on the financial guidance, maybe more for Lynne, you ended -- you currently have a little other $650 million in cash and the guidance calls for ending the year at $550 million.

So, I just want to be clear.

Does that guidance not include any new partnerships or significant milestones or any other cash inflows?

What we typically do when we do our guidance, is to provide you with very conservative guidance.

And we always do better than our guidance, which is I think what you guys expect.

So we have -- we take the things that we expect to get, which may be contingent and handicap them significantly.

So those numbers do include a little bit of stuff that's not guaranteed but very, very little.

And when we look at it, it ends up being sort of, if you get one of the things that you've handicapped, you get the whole amount because everything is discounted substantially.

I -- we're pretty conservative in our forecasting.

So, we feel very confident about the projection.

Yes, the shortest, simplest answer is, that it doesn't contain a meaningful amount of uncommitted money.

Okay, thank you very much.

And we'll take our next question from Aaron Reames from Wachovia.

Thanks for taking my questions and congratulations on the year.

Given the fact that you're maintaining your headcount, how much additional capacity does Isis have for validating targets, advancing lead candidates into the clinic?

And does that provide any limitation on the type of transactions that you'll be looking at?

Should we think that these are predominantly going to be target and lead candidate-based or would they be potentially therapeutic focused?

We believe that we can, with the group of people that we have today, add three to five new drugs a year, every year.

I know that sounds like a very remarkable statement but if you look at what we've done, you can see that all we're really talking about is doing what we've already been doing.

And as you know, we want to keep the size of Isis in the same -- in the range that we are now.

So that then -- and our strategy is to license drugs at Phase 2.

So the sorts of transactions that we're willing to consider are transactions that support moving into areas that we're not currently in.

That don't require a significant growth in our research organization.

And transactions that are strategic enough to provide real value in therapeutic areas where we are working that give our -- might give partners access to some drugs from some therapeutic areas.

In addition to transactions that might include licensing our drugs.

If you think about, over the next year to 18 months, we will have proof of concept events with quite a range of drugs.

Each of those events will be -- we'll evaluate what the data look like and whether we feel the drug is ready to partner.

And each of those opportunities presents the opportunity to generate a very large transaction, just similarly to what we did with mipomersen.

Whether we'll have a mipomersen sized transaction depends on the data.

So it's all of those.

In addition, of course, our satellite companies continue to advance.

Altair is doing great things with our aerosol drugs.

ATL continues to move along.

Oncogenics moves along.

Alnylam continues to do well.

Regulus is moving along.

And each of those enterprises provide an opportunity to generate earlier stage and later stage deals.

And each of those can contribute directly to the kinds of cash we generate and the kinds of P&L that we've put together.

So it's quite -- the thing about having so much going on is that there are all sorts of options and opportunities.

So, I don't know if I've helped you.

The answer is, if you think about Isis core, the transactions that we're willing to do are relatively focused and more limited than we have in the past.

But if you think of Isis plus all of our associated companies, you can see all sorts of transactions that contribute to our bottom line.

Okay.

That's helpful.

And then on 3715, I know that you have to see the data but if we do get positive data, would you expect then to expand the Phase 2 development program or would you consider licensing, after you just have one phase study -- Phase 2 study?

So basically, would you try to get longer duration of exposure and some experience in combination with some other agents?

How should we think about the next step after 3715?

Well, the logical next step, whether we partner the drug or not, is to go to 26 weeks.

13 weeks is just not long enough for a Type II diabetes drug trial.

And it's also logical that you'd put the drug in combination with at least metformin and possibly other drugs.

So, I think the logical next step, no matter who does it, is that sort of work.

It won't be ready for Phase 3 when we finish this Phase 2 trial.

Whether we partner it or not will depend on the quality of the data.

If we think the data are encouraging but we'll get a better partnership done if we do a single or two additional Phase 2 trials, that's what we do.

If we think that the data are even more supportive and we think that we're going to get a good deal with those data, then we'll do that.

It just depends on the data.

Okay, thanks.

And then just the last question I had, I was wondering if you could expand on -- you had mentioned the new generation 2.5 chemistry, is that in fact the new backbone or is it a modification of the [lang] and phosphorothioate bridge?

And then are any of those changes already incorporated into the SGLT2 compound or other compounds that are in the pipeline?

SGLT2 and CRP and SOD1 and the other drugs that we're putting into the clinic now are what we call 2.2.

They're all the same chemistry but have been optimized to take advantage of RNase H and they're a product of an ever more robust screening process.

And those molecules, we hope, will give us about a three to five fold increase in potency over generation 2.

So, if you think of mipomersen, the minimum effective dose of 50-milligrams a week and the therapeutic dose that we're using, 200-milligram a week, you could see that those drugs might be as potent as a dose that we might use at 100 million grams a week or somewhere in that range, maybe even less than that.

Generation 2.5 is new chemistry.

And the generation 2.5 chemistry will be a novel sugar modification.

We're quite confident of that.

And we will make that transition from the current chemistry to this new chemistry very cautiously because it represents a significant change.

We will -- we have been investing in this now for many years.

And we'll spend the next year or 18 months more evaluating multiple members of these chemical classes in mice and monkeys and lots of other species to be sure we make a good choice.

When we make that choice, we expect that chemistry to give us at least a 10-fold increase in potency over the 2.2.

So, we would hope that we might be in the range of somewhere around 10 milligrams to 20 milligrams a week or less.

That then, of course, gives us a quantum step forward in the performance of the drugs and it now makes oral bioavailability and oral administration commercially feasible.

So, that's the direction we're traveling.

We think we're close enough to talk about it.

This is the first time we have said that, sometime in the near future, we'll be bringing this chemistry forward.

That reflects the confidence that we're close and it reflects the progress that we've made over the last five or six years looking at this new advance.

Did I answer your question, Aaron?

Yes, thank you for taking the questions and I appreciate the answers.

Okay.

And we'll take our next question from Carol Werther from Summer Street.

Hello?

Hi, Carol.

Hi.

Stan, which of the trials have completed enrollment for mipomersen?

The homozygous FH trial.

So that's what we call CS5.

That's the first trial -- that's the trial we started earliest.

It's a 50 patient trial in patients with homozygous FH, in which mipomersen is added at 200 milligrams a week to maximum dose, with the lowering therapy.

And the patients are evaluated after 26 weeks of treatment.

Okay, great.

And Lynne, could you just tell us about how much you expect to spend in CapEx?

Our capital expenditures, historically, are extremely low.

Again, since we're not doing any major renovations, it really represents replacement of lab equipment and new lab equipment.

The -- this year, actually, we have a slightly larger capital expenditure because we are readying our second manufacturing suite to make launch supplies of mipomersen.

And so, while historically, our capital expenditures are on the order of several million dollars a year, this year it will be in the $10 to $15 million range.

Okay, great.

And should we expect to see the, some of the mipomersen data at Heart later this year, the homozygote?

We aren't prepared, at this point, to say more than, you should expect to -- we expect to be able to give you information in the middle of the year.

Okay, great.

Thank you.

And we'll take our next question from Eun Yang from Jefferies.

Thanks very much.

On the mipomersen clinical development, for the first $125 million Isis is going to spend for the development but after that you guys are sharing 50/50 with the Genzyme.

Does -- based on your spending assumption for mipomersen clinical development, do you think the 50/50 share could take place later this year or sometime early next year?

No.

We actually think that the drug will be on -- everything changes when the drug becomes commercialized.

So, if you're looking for the first event in those two events, we think the commercialization will take place.

Okay.

And the next question you might have disclosed in the past.

Is there a milestone associated with the success of the homozygous study that you expect maybe this year from Genzyme?

There's a milestone for NDA filing and I believe that that milestone is $50 million.

5-0?

5-0, yes.

Okay, thanks very much.

You bet.

And we'll go next to Jim Birchenough from Barclays Capital.

Hi, guys.

A couple questions.

Just one for Lynne.

Your guidance for year end cash of $550 million and at the same time, you're guiding to cash flow positive.

I'm just wondering if there's a use of cash that we're missing that takes us down from $650 to $550 million over the course of the year?

Yes, the cash flow positive, Jim, is not from operations.

It is representative of the $175 million that we got at the beginning of the year from Abbott.

Okay, got it.

Yes.

Okay.

That's clear.

And then just on the homozygous FH trial, do you have any sense right now of what percent of patients are going on to the open label extension?

Yes, I do but I'm not going to tell you.

I have to try.

And Stan, just bigger picture, at the point at which you file mipomersen with FDA, it would be the first systemic antisense drug the FDA would be looking at.

I'm wondering if you've had any discussions with them about them needing to see other antisense data?

Are they interested in safety data from other programs so they can get comfortable with the technology or just going to look at mipomersen itself?

Well, as you know, we've had ongoing dialogue with the FDA about this technology for 20 years.

We've helped developed many of the processes that are used to evaluate these drugs.

And mipomersen will actually not be the first systemic drug to be submitted to the FDA for our approval.

So our sense is that parts of the FDA are reasonably conversant with these drugs.

The manufacturing, analytical, all those sort of background things, we think are in very good shape at the FDA.

They understand what we do and how we do it.

And as a general rule, like what we do.

So we -- the things that can often cause problems with drugs, especially new classes of drugs, we're not very concerned about.

And so, our thinking is that the focus of the FDA will be pretty specific on mipomersen from a safety and efficacy point of view.

They will of course have background information on the performance of lots of other drugs, that in contrast to small molecules where you don't learn anything, that information will help inform them.

But I think the safety and efficacy will be focused right on mipomersen and whether it adds value to patients with the severe cardiovascular risk factors.

Great, and just one final question.

I know in the past there's been some enthusiasm about oncology targets like survivin and clusterin.

I haven't heard a lot about any of those programs moving into pivotal programs or when we might see data.

Could you maybe update where your partners are at with the oncology side of the business?

Well, one of the most exciting reports from us and our partners last year was Oncogenics' randomized Phase 2 trial, in which they showed when you added OGX-011 to docetaxal in first line treatment of prostate cancer, you've got a dramatic improvement in survival.

That's really quite exciting.

And I think that -- again, I think those data need to be reviewed in detail and they need to be reproduced.

But if they are reproduced, I think it will represent really quite an exciting breakthrough in prostate cancer.

So, we're quite encouraged by that and Oncogenics is ready to begin Phase 3 trials.

With regard to survivin, Lilly is completing important trials.

And we hope that Lilly will be discussing some of their results with survivin.

We're certainly very encouraged by what we're hearing.

So we are very confident now that with second generation antisense drugs, we are getting good concentrations of drug in human cancers, reducing targets.

I think the demonstrations of that with clusterin, survivin and others is very compelling.

And if we have the right target, target reduction then leads to the biological effects that we hope -- that will have an effect on cancer.

So we're quite -- we're reinvigorated about the notion of these drugs for cancer treatment and that's why we've re-initiated our cancer program.

Very, very encouraged, Jim.

Thanks, Stan.

I think with that, we're at about an hour and we ought to bring the question and answer period to a close.

So, Connie, if you can do that?

Thanks, everyone, for your interest and we will keep you posted as we progress this year.

This concludes today's conference.

We thank you for your participation.

You may now disconnect.