Kristina Lemonidis – Director, Corporate Communications Stanley Crooke – Chairman and CEO Lynne Parshall – CFO and COO

Yodi Morango [ph] – Collins Stewart Eric Smith – Cowen and Company Eileen Flowers – Jefferies & Company Ted Tenthoff – Piper Jaffray & Co. Charles Polsky – William Harris Investors

:

Good afternoon, and thanks everyone for joining us on today’s conference call to discuss our third quarter financial results. Lynne will discuss our financials, and after that I’ll give you a brief update on our activities for the rest of the year. Joining us on the call today are Lynne Parshall, Chief Operating Officer and CFO; and Kristina Lemonidis, Director of Corporate Communications. Kris, will you read our forward-looking language statement please?

Thanks, Stan. Good afternoon everyone. A reminder to everyone this web cast includes forward-looking statements regarding Isis’ financial positions and outlook, Isis business, the planned commercialization of mipomersen and the therapeutic and commercial potential of Isis technology and products in development. Any statement describing Isis’ goals, expectations, financials or other projections, intentions or beliefs 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 in 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, and 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, 2010 and its most recently quarterly report on Form 10-Q , which are on file with the SEC. Copies of these and other documents are available from the company. With that, I’ll turn the call over to Lynne.

Thanks, Kris. As usual, I’ll assume that you’ve read the details of the third quarter financial results in our press release, and I’ll of course be happy to take questions at the end of today’s call. We continue to make excellent progress this year. Our most notable success has been the submission of the mipomersen or rather Kynamro marketing application to the EMA. With this submission we are one step closer to commercializing Kynamro, and our more recent activities continue the momentum following the NDA submission. The three upcoming Kynamro activities that you should focus on are first Genzyme remains on track to file an NDA this month. Second Genzyme is actively preparing to launch Kynamro next year in both the US and Europe, including expanding its already leading commercial launch team. Third Genzyme has reached an agreement with the FDA for a special (inaudible) assessment on the design of the FOCUS FH study. This 12 month study will start this year, and is designed to support the following goals. Expansion of the FH population in the US can include severe heterozygous FH offering an alternative dosing regimen of 3 times a week dosing, so that we can offer our patients different dosing options. And potentially broadening the FH indication beyond severe in Europe. We are enthusiastic about the opportunity to invest to expand the Kynamro profile in its potential markets. In addition to Kynamro our progress this year is also evident in the maturing of our pipeline. We initiated clinical development on five drugs and two new drugs and continue to report the encouraging data for many of the drugs in our pipeline. We’re just beginning a busy fourth quarter in which we will be reporting clinical data on a number of our drugs. And Stan will provide more information on that in his part of the call. We believe that this fourth quarter will be an exciting time for Isis and we look forward to sharing these successes with you. Now let us take a few minutes to look at our financials in more detail starting with our 2011 revenue. as you probably heard me say before, our revenue consists of several different components, including amortization of upfront fees we receive from our partners, R&D revenue of this quarter collaborations, milestone payments, license fees plus revenue we earn from other miscellaneous transactions. For example, our revenue in the first nine months of 2011 included more revenue from GSK compared to 2010, due to the timing of the amortization of the upfront fee from GSK, which began in April 2010. However, the increase in revenue from GSK was offset by less revenue from BMS and Alnylam as the amortization of upfront fees from these collaborations ended in 2010. As our partner drugs advance in development, we earn milestone payments from our partners, but the timing of these payments fluctuate. This year so far we have earned approximately $11 million in milestone payments, compared to $13 million this time in 2010, and we have recorded the $5 million payment from GSK related to our alpha-1 antitrypsin drug in the fourth quarter. Our acceptance for the first nine months of 2011 are right where we projected. We predicted a modest increase in our expenses in the second half of 2011 primarily due to the drugs in our pipeline advancing into and through clinical studies. As we have been given longer and larger studies, the costs associated with the continued development of these drugs increases. Moving these assets to key value inflection points is a large part of our business strategy. With this strategy we have remained financially strong in today’s economy. We now have over 2000 drugs in our pipeline and by the end of the year we will have more. Many of these drugs already are or will be moving into Phase II studies next year setting us up for an exciting 2012. And with so many of the drugs in our pipeline entering late stage clinical development next year, we expect our expenses to be modestly higher. We are close to meeting our $125 million spending obligation for Kynamro, and once that happens external development costs for Kynamro will be shared 50:50 with Genzyme. So although we are projecting an increase in our expenses next year, our cost for Kynamro will not contribute to this increase. Also it is important to note that Genzyme is currently paying for all marketing and sales costs and will continue to do so until there is Kynamro revenue, which will be used to cover Kynamro expenses. You will recall that one component of our revenue and cash projections for 2011 is the $25 million that we will earn when the FDA accepts the Kynamro NDA filing. Genzyme plans to file the NDA this month. If the FDA takes the full 60 days to accept the filing that milestone could be achieved very early next year, as opposed to late this year. Obviously this will not present any real change to our financial position, but it could affect our 2011 NOL and cash guidance. So we have done everything we have set out to do this year, including submitting the marketing application for Kynamro in Europe, and very soon in the United States. And the year is not over that. By the end of 2011, we will have made significant advances in many of the drugs in our pipelines, plus we identified our next-generation technology, and moved the drug into development that incorporates this technology. And finally we have been very successful with our partners. We have advanced drugs into development in our GSK collaboration earning $13 million in revenue from GSK this year. So with that I will turn the call back over to Stan.

Thanks Lynne. Our primary focus in 2011 has been and remains moving mipomersen towards the market. We have completed the submission for marketing approval in the EU and as Lynne mentioned Genzyme and we are finalizing the US submission, and the US submission will be filed this month. The interactions we have had with both the US and EU regulatory authorities have been productive and give us confidence that our filings are appropriate and approvable for the indications we are seeking. We believe we have a comprehensive of registrational regulatory dossier. Mipomersen is focused on patients within obvious, severe unmet medical needs, FH is a stable cardiovascular disease. We have completed 4 randomized Phase III trails, each study showed compelling efficacy and an acceptable safety profile, each study demonstrated that mipomersen has unique lipid lowering profile. Kynamro was the only drug that lowers all atherogenic lipids. Our long-term open-label extension study has demonstrated continuing efficacy, and consistent safety. Our preclinical dossier is robust, and other parts of the filing such as CNC are very strong. Recently a circulation published in an article written by Doctor Frederick [ph] and colleagues. In this article they have reported that the effects of lipids lowering drugs in the life of homozygous FH patients, the study showed that a mean reduction of 26% in LDL cholesterol was associated with delayed cardiovascular events and prolonged survival in homozygous FH patients. This answers a question that we have been asked quite a number of times, and that is can the linear relationship of LDL cholesterol that cardiovascular risk be extrapolated to patients with extremely high levels of the LDL-C and in particular extrapolated the homozygous FH patients. The answer is an unequivocal yes. In this group, a 26% reduction in LDL cholesterol has extended the average patient’s lifespan from 18 years to 32 years. Imagine dying of cardiovascular death at 18. Now, you will recall that in our studies we have shown in the range of 26% to 37% reduction in LDL cholesterol, and we get that of course when we add mipomersen on top on the reductions produced by statins and other drugs. It is exciting to think then about what the addition of Kynamro means for these patients. If you add mipomersen’s effects, which is what we are doing, we are adding mipomersen to existing maximum lipid lowering therapies, you can imagine that these patients will live until they see their children graduate from college. This analysis of homozygous FH patients over the last 40 years highlights the importance of early diagnosis, and the need for new drugs to be added to existing drugs, to extend and to improve the quality of these patients’ lives. Although the initial indications alone from mipomersen represent a significant commercial market for Kynamro, we also have our eyes on the future. We think there is a great opportunity for significant long-term commercial growth for Kynamro, and that is why we are excited about getting the FOCUS FH study under way. We now know exactly what we need to do to achieve expanded patient populations. As Lynne said earlier, Genzyme reached an agreement with the FDA on the design of the next Kynamro study throughout a special protocol assessment work, SPA. This study is designed to achieve three goals, support the expansion of the FH population to include severe FH in the US, supporting an alternative dosing regimen of 3 times a week. We think providing patients this option should have a positive effect on compliance, and the study is designed to support potentially broadening the FH indication in Europe beyond severe FH to the next level of heterozygous FH patients, those with LDLs in excess of 160 mg per deciliter. As we have said, this will be a 12 month study with fewer than 500 patients that will include both severe and less severe heterozygous FH patients, and it will include statin intolerant patients. This study is planned to begin by the end of this year. We are also pleased with the preparation and progress being made at Genzyme and Sanofi to launch Kynamro. There is a great deal of work to be done to expand awareness of the disease and get these patients into the hands of lipidologists. This is the main focus of the marketing group at Genzyme as they work with the National Lipid Association and other patient efficacy groups, to increase awareness of this devastating disease. An important objective of the NLA and other groups is to ensure that FH patients are diagnosed earlier, and treated more aggressively than they are today. So that is mipomersen. Now let us look at our pipeline, and this has been a year of exceptional growth and a lot of positives across many therapeutic areas in our pipeline. It has been our strategy to create a cardiovascular disease franchise comprised of drugs that target all the key components of cardiovascular disease such as various atherogenic lipids, inflammation and thrombosis and we are doing exactly that. We already know that mipomersen has a great effect on LDL cholesterol and all the other key atherogenic lipids. Our CRP inhibitor significantly reduced CRP in a Phase I study in normal volunteers becoming the first selective CRP reducing agents to be shown active in man, a 70% reduction in normal volunteers is really remarkable. Because CRP levels are increased in many inflammatory conditions the potential therapeutic benefit of the selective CRP lowering agent could be very significant in cardiovascular and many other diseases, and our broad Phase II [ph] is underway. Our APOCIII drug is particularly exciting. APOCIII and triglycerides are both independent cardiovascular risk factors. Our drug we hope will be a very potent, selective inhibitor of APOCIII and will reduce triglycerides. Like mipomersen we will know in Phase I – with our Phase I data whether we have an effective drug. We are measuring both levels of APOCIII and triglycerides in blood repeatedly and we will report the data from this study next month. Similarly next month, we will announce phase 1 data on our factor 11 drug, the great addition to our cardiovascular franchise. Again we will know in Phase I whether our drug lowers factor 11 and if it is likely to cause any bleeding. Don’t forget that this drug in pre-clinical studies demonstrated potent anti-thrombotic activity with no increase in bleeding, and human beings who have no mutations for factor 11 don’t bleed. So there is a lot of reason to believe that this drug could become an ideal agent to treat unwanted thromboembolic events. Our metabolic disease franchise has also matured significantly this year. We now have four drugs to treat type II diabetes progressing in clinical trials, and we will soon initiate clinical trials on our first anti-obesity drug that targets FGFR4. Very late this year, early next year we will also report on SGLT 2. We continue to expand our cancer franchise. This year we added our first generation 2.5 chemistry drug targeting STAT3 to our pipeline. The two Phase II trials of our EIF4E drug are progressing nicely, and of course our partners at Eli Lilly and OncoGenex continue to make progress on our partnered anti-cancer drugs. Similarly we are very pleased with the progress of our severe and rare disease franchise this year. We announced a new development candidate from our GSK collaboration targeting alpha-1 antitrypsin. We initiated Phase I studies in normal volunteers on our TR drug. In fact we will be reporting data on that Phase I study in the next quarter as well. This again is a target that is readily measured in blood. So at the end of Phase I, we will know if we have an active agent. And as we move ahead working with our partners at GSK, we believe we have a very rapid route to the market with this drug. We are very pleased with the progress of our neurodegenerative franchise. We will begin our Phase I study in patients with spinal muscular atrophy very shortly, and we continue to move forward on our SOD1 study in patients with ALS. Finally, we plan on advancing three additional first in class drugs into our development pipeline by the end of the year, and because of all this activity, we plan to have an investor call in December to talk about these exciting new entrants. With all the progress that we have made this year, particularly with all the data that we could be reporting in the fourth quarter on so many important clinical trials, we feel that it will be important to summarize that progress, and to do that we plan to host an R&D day on January 5 in New York to help you digest the significance of all these achievements. So please save that date with mipomersen commercialization on the horizon and all these exciting new drugs moving through clinical trials and generating important data, the end of 2011 promises to be very important for Isis and 2012 promises to be another full and exiting year. And with that I want to thank you for joining us today. We will now open up the call for Q&A. Kris, if you can set us up please.

(Operator instructions) Our first question comes from the line of Salveen Richter of Collins Stewart. You may proceed. Yodi Morango - Collins Stewart: This is Yodi Morango [ph] sitting in for Salveen. I wanted to ask about the reason for the change in dosing frequency to 3 times a week in FOCUS FH and how do you see that affecting compliance, and also the risk of ISR, and I have a follow up question.

We are not changing dosing. This is a continuous step – the continuation of the plan that we laid out years ago. We have weekly dosing. We have already shown that daily and three times a week, and our objective is to both – in this study we will be doing weekly dosing, as well as three times a week dosing. And the objective with the three times a week dosing is to provide patients the option of using the drug weekly or more frequently and giving the patient as many options as possible with our drug, to find the most convenient way to administer for each patient being different is what we think is the right way to provide the maximum in compliance. So there is no change at all in the plan that we have laid out. We are just pursuing the plan as we described over the last several years. Yodi Morango - Collins Stewart: Thank you and how many arms will this study have?

It will have a once a week, three times a week, placebo arms. Yodi Morango - Collins Stewart: Thank you and one quick follow-up question, you mentioned on the last call and also today that Genzyme’s marketing strategy is focused on educating physicians and patients, what has been done to date on the physician education front, but also on the payer front? Thank you.

I will answer briefly and then Lynne can provide more detail. I think the most important thing that has happened over the last couple of years has happened independently of Genzyme, and also has been facilitated by Genzyme and that is the identification of FH as a significant cardiovascular disease that is tremendously under diagnosed. If you look at the guidance that has been published by the National Lipid Association you will see that it encourages early diagnosis, cascade screening, and the much more aggressive treatment as well as referral of patients to lipidologists. In addition, Genzyme is engaged in quite a number of focus groups on other activities that are contributing and Lynne you probably want to add some more to that.

Sure. Genzyme has actually now for the last year and a half or two years had a significant presence at all of the major medical meetings focused on cardiovascular health and on lipids. They have sponsored CME events and again they are focused in working both at medical meetings as well as with patient advocacy groups is on early diagnosis and aggressive treatment of these patients and identifying them and getting the patients into care of lipidologists, who are best suited to treat them. In addition of course, both in the US and in Europe, Genzyme is working with the various payer agencies. They have a very strong infrastructure to do that augmented of course now by the Sanofi infrastructure, and that has been an ongoing effort for quite some time.

Next question please.

Our next question comes from the line of Eric Smith of Cowen and Company. You may proceed. Eric Smith - Cowen and Company: Good afternoon, and thanks for taking my questions. Lynne in terms of the potential for the Kynamro acceptance to slip into Q1, if it does we will just assume that you will fall a little bit short, $25 million short of the operating loss guidance, and cash year-end guidance that you have previously given. Is that how we should think about that?

Yes, I think that is a fair way to think about it. Eric Smith - Cowen and Company: Okay, and then Stan on the SPA, what does it say exactly you need to achieve in this 12 month trial in order to get the broader, less severe label for heterozygous FH in the United States. You just need to lower cholesterol or achieve a certain reduction or have some kind of safety?

Yes, Eric, all we are doing is the same thing that mipomersen has done in 4 previous randomized trials, and in the long term open level study. It boils down to lowering cholesterol in exactly the way we did before, and getting additional safety experience. Eric Smith - Cowen and Company: Is there anything about the profile to date safety wise that makes this a risk in terms of the upcoming trial?

I am as confident as I have ever been in the clinical trial with this disease, and 100% successful. Eric Smith - Cowen and Company: So, just simply showing the same safety profile you have seen in the previous four pivotals that would enable you to get approval in the broader population?

Yes, and that is exactly what I have been saying for some years that is the message we got from the European authorities, and now we have agreed with the FDA on specific study design and numbers of patients, and the requirements for meeting the FDA’s needs as well. Eric Smith - Cowen and Company: And if this trial is…

All good news. It is all really good news. Eric Smith - Cowen and Company: Clearly. If this trial then provides the expected result, how much broader could the European label become in terms of less severe heterozygous FH?

Of course, nothing is certain until you actually sit down and negotiate the label, but I think I mentioned that we would hope that we would achieve any patient who had greater than 160 LDL cardiovascular events on maximum lipid lowering therapy. Eric Smith - Cowen and Company: Okay, and the last question, I’m just not sure I’ve heard the date of the R&D day in January, was that the 5th or 25th of the month?

January 5, right after the first of the year. The reason for that Eric is that we just have so much important data coming out right in the fourth quarter with APOCIII, factor 11, TTR, SGLT 2, all the other things we just think it is going to be a lot of information for people to digest, and we’re going to have to help you understand it. Eric Smith - Cowen and Company: Okay, we will be top line press releasing some of that, or will we wait until January to see?

No, we will be putting out press releases on most of it, probably, yes, you will see a spate of press releases coming. Eric Smith - Cowen and Company: Okay, thanks a lot.

Lynne do you want to add anything to or subtract anything from what I said to Eric?

: The FDA wanted us to treat more patients with the drug, reflecting the very much larger market that is represented by the severe FH patients. But the study looks very, very much like all the other studies we have completed. Eric Smith - Cowen and Company: I’m probably going to push my luck with this last question, but is there any kind of expected time line in enrolment and gathering data from the trial or is it too early to say?

I think it is too early to say. Once we start enrolling patients, I think when we get a few months into the enrolment, we will have a much better handle on it, but I hate to project right now. Eric Smith - Cowen and Company: Thank you.

I will say that there is a lot of enthusiasm for mipomersen and the trial, and so getting underway. And you know, you don’t need to listen to me, all you have to do is look at all the reviews that have come out about mipomersen over the last couple of years, and you can get a sense of how interested the cardiovascular community is in the drug. Eric Smith - Cowen and Company: Thanks and good luck.

Yes. Great news that is the bottom line. Great news.

Our next question comes from the line of Eileen Flowers [ph] of Jefferies & Company. You may proceed.

Hi, it is Eileen dialing in for Eun Yang this evening, can you talk about whether you anticipate a 10 month interim review for mipomersen at the FDA? Thanks. Jefferies & Company: Hi, it is Eileen dialing in for Eun Yang this evening, can you talk about whether you anticipate a 10 month interim review for mipomersen at the FDA? Thanks.

Did you understand the question Lynne?

Yes, the question is what is the length of the review, I think until we file and have a chance to talk to the agency about the review time, it is probably premature to contemplate that.

Okay, thank you. Jefferies & Company: Okay, thank you.

Our next question comes from the line of Ted Tenthoff of Piper. You may proceed. Ted Tenthoff - Piper Jaffray & Co: Great. Thank you very much on the good news update looking forward to a busy fourth quarter. I'm actually out in San Francisco at the liver meeting, and one of your competitors, Santaris is going to be reporting some data on miR-121 in HCV. And maybe you could give us some update on what the litigation there is and also on the good news that has been coming out of Regulus of late?

There is no update on the litigation. It is our belief that the miR-122 we own, we and Regulus and that is based on the patents that we have. So we are quite excited to see the positive data that Santaris is generating, and we will pursue the appropriate steps to assure that are patents are in force as we always have.

Thanks, thanks. And we saw that nice paper out of Regulus recently. Any other updates from those other things [ph]?

Making good progress. Understanding how the drugs work, beginning to understand the microRNA pathway and how to exploit it to get a therapeutic index that is appropriate. So, we are very pleased with where Regulus stands, and we are very pleased with the patent position that we hold. Ted Tenthoff - Piper Jaffray & Co: Great. Thanks for the update. It has been exciting progress.

And as Lynne mentioned, I think we’re very excited to see the NDA going in this month for Kynamro. That is another big event for us, and so it makes for an exciting fourth quarter and a great year for us. Lynne, do you want to add anything to the questions about litigation?

No.

(Operator instructions) And our last question comes from Charles Polsky of William Harris Investors. You may proceed. Charles Polsky - William Harris Investors: Hi, Lynne and Stan. Thanks for taking the question, and it is a small question, so as it relates to dosing mipomersen three times a week, is there any accumulated data on patients in other trials maybe who have been dosed three times a week and does the smaller dosing tend to result in less injection site reactions that are accumulated patient treatment you have so far?

Yes, Charles. We did a study where we compared daily, three times a week and weekly dosing for both B-100 reduction and LDL reduction, and other lipid reduction, as well as tolerability and injection site reactions. And as you would expect, as you go to lower doses you have less injection site reactions. We are not very concerned about the injection site reactions, weekly or whatever. So yes, as you go to lower doses administered more frequently, you have less injection site reactions, but of course you are giving more injections. And so it is a balance. We think some people will like giving themselves smaller injections three times a week, and we think some will like giving themselves a larger injection once a week and will just depend on the patient. And the whole goal here is to provide improving presentations of the drug and additional options for patients, so that each patient can find his best way of getting the drug. We are not doing daily in this study because we want to continue to look at the proper presentation of daily administration, the right injector and all that, and so that is taking some additional time. But eventually I would expect that we will also offer daily injections as well. But the data are very clear. As you would expect, the pharmacokinetics of the drug support weekly administration at one dose, thrice weekly at another dose, and daily injection at a one seventh of the weekly dose just as the pharmacokinetics will tell you. Charles Polsky - William Harris Investors: Thanks Stan.

And we have no further questions at this time. I would now like to turn the call back over to Dr. Crooke for any closing remarks.

Well, thank you very much. We think that we are in a very exciting moment for Isis. And in this call, we have told you that Genzyme and we will be filing our NDA this month for Kynamro. We have told you that the FDA has approved our special protocol assessment for the study that we believe will allow Kynamro to advance to much larger markets. We told you that we will be reporting data, important clinical data on multiple drugs over the next quarter, and we look forward to providing all of that information to you as this next quarter unwinds, and to summarize it and contextualize it for you in January 5 in New York. Thank you very much.

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