ISIS Pharmaceuticals' Management Presents at 2013 Barclays Global Healthcare Conference (Transcript)

| About: Ionis Pharmaceuticals, (IONS)

ISIS Pharmaceuticals, Inc. (ISIS) 2013 Barclays Global Healthcare Conference Call March 13, 2013 2:00 PM ET

Executives

Bruce Turner - Vice President, Corporate Development

Analysts

Bruce Turner

Isis Pharmaceuticals. This is our forward-looking statement. So we guide or caution with regards to any statements we may make today.

First, I am going to start with an overview and just describe some of the key messages that I would like to cover during my talk today. We are going to briefly talk about KYNAMRO or mipomersen which, as some of you may know, was recently approved by the FDA on January 29 for the indication of homozygous familial hypercholesterolemia. For Isis, this was a landmark approval since this it’s the first systemically delivered antisense drug that’s been approved.

I am going to talk to today about our maturing and developing pipeline which includes five drugs with a launch potential in the next five years, nine drugs with Phase 2 or Phase 3 data plans for either 2013 or early 2014. In addition, we have three Phase 3 programs that we plan to initiate later this year or early in 2014.

We committed to develop three new drugs which will enter the pipeline in development each year. We are going to talk about our growing severe and rare disease program franchise which we have begun to see success in already.

We will briefly talk about our Generation 2.0 drugs and new screening methods that we are now using to develop newer antisense drugs that are more potent and better tolerated than both prior 1.0 generation and earlier 2.0 generation drugs.

Finally we have a new backbone in our Generation 2.5 drugs which we will discuss. We are going to talk about our partnering success that we have had in 2012 and which we hope to continue in 2013 and some of our goals for 2013 as well.

This is our pipeline as of March 2013. We have 28 drugs in either clinical or research development at Isis. Our therapeutic areas are now extensive and include, in addition to cardiovascular, a severe and rare drug franchise with multiple drugs in clinical and preclinical development. A metabolic franchise, an oncology franchise and finally an inflammation franchise and we recently reported this morning Phase 1 data from the lead compound there which is an antisense inhibitor to C-reactive protein or CRP.

We also have a number of other drug which are preclinical and which will enter clinical development later this year. They include drugs for coronary artery disease, clotting disorders, liver diseases, Angioedema, NASH, as well as cancer.

KYNAMRO or initially known as mipomersen is the first systemic antisense drug that’s been approved. It's given subcu. We received the $25 million milestone from Genzyme, Sanofi upon approval. It was approved on January 29 and commercial activities are underway. So we are qualifying physicians. Scripts have been written. We are focusing on a message with regards to this compound of simple easy to use at home subcu administration with no drug-drug interactions, no requirements for vitamins or special diets and things are going well early in its launch.

We are also investing in the future for KYNAMRO. We have a Phase 3 FOCUS FH study ongoing in patients with severe heterozygous FH. Patients are being enrolled. This trial is under an SPA and will help us with approval in the U.S. for patients with severe heterozygous FH. The projected completion date is late 2014.

We have a number of five potential drug launches between now and 2017. As some of you may know, we have a drug that just entered Phase 3 development with our partner GSK for TTR amyloidosis. The indication here is patients with familial amyloid polyneuropathy. There are approximately 10,000 of these patients.

The second drug with potential launch over the next several years is a drug we are developing in collaboration with Biogen Idec. This drug is an antisense inhibitor that impacts splicing. So its our first drug that targets a splicing mechanism. This drug targets the SMA protein or the SMN gene. There are approximately 35,000 newborns and children with this disease worldwide and it’s the targeted agent that is specifically being developed for this indication.

Our third drug, ISIS-APOCIII is a wholly owned asset by Isis. It is currently in Phase 2 in two Phase 2 programs and a Phase 3 program that will start either later this year or early in 2014.

The fourth drug is the OncoGenex drug which is an antisense inhibitor to clusterin which is in late Phase 3 development by partners Teva and OncoGenex. We should have data either late 2013 or early 2014 with regards to survival in metastatic hormone refractory prostate cancer patients.

Our last drug which is in Phase 2 development is in collaboration with Pfizer and Excaliard. This is a locally administered drug to prevent scarring in patients undergoing biopsies, c-sections or breast surgery to reduce scarring.

This is one of the drugs that we just discussed which is TTR, transthyretin amyloidosis. As some of you know, it’s unstable genetic disease affecting approximately 50,000 patients worldwide. TTR mutations cause and unusual tetrameric folding of the TTR protein. It causes it to be unstable. Monomers develop causing plaques which extend from the periphery inward encasing nerves, heart, kidneys and other organs eventually causing cell death. The age of onset is between 30 and 50 years old. The life expectancy after diagnosis is approximately 10 years. As I mentioned, we are now in a Phase 2/3 program with GSK.

The other indication that we will be developing going forward, is an addition for patients with familial amyloid cardiomyopathy. This is a larger indication, approximately 40,000 patients worldwide, a shorter life expectancy and we will discuss further details about this later this year, early next year.

This is the Phase 1 from TTR amyloidosis. These are in healthy volunteers who we were able to in a dose-dependent way. As shown through these graphs, reduced wild type TTR protein. So we showed sustained reduction. Patients were given subcu loading doses of this drug on days 1, 3 5. Thereafter were injected subcu weekly with this drug. As we show here, as we go from 50 mg to 100 mg, 200 mg, 300 mg, 400 mg show nice dose-dependent rolling of plasma TTR protein. Importantly, this is a relatively new drug where we have had to develop new screening techniques to identify (inaudible) receptors and you can see we have a very low incidence of flu like symptoms and mild injection site reactions. So it dramatically improved over earlier drugs developed using the 2.0 backbone.

The Phase 3 program is ongoing in partnership with GSK. It’s a randomized double-blind placebo-controlled phase 2/3 study in patients with FAP. Approximately 200 FAP patients at 20 global sides would be randomized to receive 300 mg of weekly TTR or placebo in a two to one randomization fashion. We will using a neurologic dysfunction and quality of life endpoint known as the (inaudible) score for the primary endpoint of this study.

Again, we believe this drug will have a rapid path to market. The possibility for orphan pricing. We believe the potential for best in class treatment for both wild type as well as mutant TTR protein. The message will be clear. Again, a message that’s not that dissimilar from KYNAMRO. There will be weekly at home self administered subcu dosing. The development plan for cardiomyopathy is in progress. The economics are attractive with $80 million in upfront payments in prelicensing milestones. Additional licensing fees, regulatory and sales milestones. Again, remember that GSK has an option to license this drug after the Phase 2/3 data and so that will result in a large payment in addition to significant double-digit royalties on net sales.

Our next drug that’s in later stage clinical development on it ISIS-SMNRx for spinal muscular atrophy, known as SMA. It’s a severe genetic neuromuscular disease affecting children. There are currently no approved drugs and no drugs in development that directly impact the genetic cause of this disease. It’s the been number one genetic cause of death in infants. They die of respiratory compromise. Its characterized by progressive muscle atrophy and loss of the spinal motor neuron. It is a rare disease. It affects about 30,000 to 35,000 children in the U.S., Europe and Japan. As I mentioned there are no currently approved therapies.

This is our first drug that modulates an RNA processing defect to positively impact disease. So what happens here is patients have loss of SMN1. It turns out that we have a related gene SMN2 that produces only about 10% of normal SMN protein because of inappropriate RNA processing. So what our oligo does is it allows the inclusion of exon 7, as shown in the diagram on SMN2 gene on your right side. That that does is it allows more functional SMN protein to be transcribed and translated. So instead of 10% of functional protein, its more like 60% to 80% of functional SMN protein is produced.

We have a Phase 1 study that is now completed that will be presented next week at the American Academy of Neurology, March 20, in San Diego. It was an open label, single dose, intrathecal administration of ISIS-SMNRx. The intrathecal dosing, we have said, is well tolerated. We have shown infrequent dosing as demonstrated. Importantly, we had a press release around JPMorgan in early January demonstrating that there were some correlations between the motor function response and dose which we will highlight an oral presentation next week. We had four cohorts, 1 mg, 3 mg, 6 mg and 9 mg. They were treated on Day 1 and evaluation periods for the lower doses were at four weeks. For the higher doses were at 12 weeks.

We have a second study, a Phase 1b/Phase 2a study that is ongoing, again, in SMA patients between the ages of two and 15 in this study. There are three cohorts, eight patients at 3 mg, eight patients at 6 mg, eighth patients at 9 mg. The patients are being treated. The lower doses on Day 1. Again the lower doses on Day 29 and the higher dose on Day 85. So again, all three doses are being treated on Day 1 and all three doses are being treated on Day 85.

The purpose of this study is to not only show safety but also combined with some of the nonhuman primate to come up with an effective dose and dosing regimen for our Phase 2/3 trials, which are intended to start later this year or early 2014. So the drug has been granted orphan drug status in the U.S. and in Europe and fast track designation in the U.S.

The two pivotal trials, the smaller study will be an infant onset study, again starting later this year. There will be a smaller study, approximately 50 patients. A second larger study of about 150 patients will be the childhood onset. The type 2 and the 3. Again this will be a phase 2/3 study. Both of these studies are intended as registration studies. We have attractive economics that are associated with SMN. Again it has been partnered with Biogen Idec.

There is $74 million in upfront payments in prelicensing milestones. There will be an additional $225 million in licensing fees and milestone payments which we have received not yet to date. There will be significant double digit royalties associated with net sales of this drug.

Our next drug that’s in late stage development and could be launched in the next five years is ISIS-APOCIII for patients with severe hypertriglyceridemia. APOCIII regulates the hydrolysis of triglycerides through LPL lipase. No other drugs before has been developed that directly targets APOCIII. Our Phase 1 data which I will show you shortly was very intriguing.

There are more than 200,000 patients in the U.S. and the E.U. with triglyceride levels above 880 mg/dL. So it’s a good size population. These patients are at significant risk of developing recurrent acute pancreatitis, often requiring multiple hospitalizations, surgeries and eventually leading to endocrine dysfunction in the so-called brittle diabetes. These patients also are at high risk for cardiovascular disease.

Recent genetic studies show that patients with mutations in these genes which have loss of function of APOCII have very low levels of coronary artery disease suggesting that APOCIII and regulation of triglycerides are critically important in not only regulating triglyceride levels but long-term outcome. Standard therapy to treat severe hypertriglyceridemia include niacin, fibrates and fish oils.

Many of these patients are on maximally tolerated levels of these drug and still have difficulty controlling their triglycerides. So the potential for broader utility in cardiovascular disease, metabolic syndrome and potentially diabetes management.

This is an example of the APOCIII levels in a Phase 1 study in patients, healthy volunteers that had normal levels of APOCIII and triglycerides. As you can see here we show a dose-dependent decrease in triglyceride levels. So at the maximal doses of 200 mg and 400 mg, we show 40% to 45% decrease in triglyceride. In other curves, which I curves which I am not going to have time to show here today, we show a 60% to 70% decrease in APOCIII levels. Importantly there were no clinically significant increases in liver enzymes, flu like symptoms, and a very low incidence of mild injection site reactions.

We have two Phase 2 study which we will be completing later in 2013 for APOCIII. The first is in patients with significantly elevated triglyceride levels above 440 mg/dL but less than 2000 mg/dL. We are looking at three doses in this study, 100 mg, 200 mg and 300 mg. We will have data in the middle of this year.

A second smaller study in diabetics, looking at a single dose administered weekly 300 mg per week. Again looking at triglyceride APOCIII levels and some insulin sensitivity endpoints. We should again have data from this study a little later by the end of 2013.

We believe there is a rapid path to market. We are currently developing a Phase 3 program for patients with severely elevated triglyceride levels. Le will detail that the street later this year. I think what's important to note here is this remains an Isis wholly owned program.

So we have a number of drugs that are in clinical development and here we show all the drugs with important Phase 2 or Phase 3 data in later this year or early 2014. besides when I mentioned, I think it is important just to briefly, just to let you know that OncoGenex and Teva, again will have data from OGX 011 later this year or early next year. It’s a survival endpoint.

We will have data this year on our antisense inhibitor to FXI for thrombosis following total knee replacement and that’s comparing that with Nadroparin. Importantly to remember, this is another Isis wholly owned program that has not been partnered. We presented a press release today showing positive data on our endotoxin study for CRP. So this is the first drug that directly targets CRP.

Following up on that will be a study later this year in patients with RA that are on stable RA related drugs and will be treated wither with or without the antisense inhibitor CRP and we will be looking at some of the typical ACR endpoints that one typically measures in patients with RA and correlating that with CRP.

We will also be presenting later this year data on STAT3 which is a transcription factor that is mutated in patients with different types of liquid in solid tumors. That program has been licensed, as you may remember, to AstraZeneca in December of this year. We are now doing a larger study in patients with lymphoma. There will be data on objective response rates to that drug later this year or early next year.

Again, advancing the pipeline, numerous other drugs just to highlight. We have a large metabolic franchise in addition to our three drugs that are being for rare and orphan diseases. So just to refresh your memory again, we have drugs for both Type II diabetes, Cushing's syndrome as well as cancer and some of the other drugs that I have described. Many of these drugs remain wholly owned by Isis and are progressing through our pipeline.

So we are advancing the technology at Isis and so not only do we have 28 drugs in clinical and preclinical development but we are working on new mechanisms. So, an example of the RNA processing or splicing mechanism that we been successfully been able to target was our program with SMA. So as you can imagine there are dozens of other diseases that are caused by interference with, or disruption by splicing. Lo there are many new diseases that we can target in addition to single-stranded RNAi.

We are also pursuing new methods of delivery of these oligos. To the intrathecal method, an example of that was our clinical trials and development of SMA. We also had intradermal administration of our oligos now when we were doing that, as I said, in collaboration with Pfizer and Excaliard for our drug that targets a local growth factor that prevents scarring.

As I mentioned before we now have better screening techniques even for our 2.0 generation antisense drugs. These better screening techniques allow us to develop drugs that for APOCIII, our drug for TTR amyloidosis, our drug for FXI and in fact, we even have a new chemical push on the chemical backbone which we have labeled 2.5 generation chemistry. Our first drug has been brought into main using that chemistry. Examples of that are our Phase 1 data with STAT3 which will highlighted later this year.

This is an example of our advancing antisense technology. So this is comparing target protein reduction after four weeks of treatment comparing it with KYNAMRO which is an older drug. It was developed about 12 years ago. As you can see, if you focus just on the first slot there on APOCIII, you could see the doses that we are targeting for this drug is somewhere between 200 mg and 300 mg. You can see a 70% to 75% improvement in potency relative to KYNAMRO using the same 2.0 chemistry but with improved profiling of this drug.

In addition to improved potency, if you look below for APOCIII, you could see that there were 90% fewer injection site reactions and to date through the Phase 2 program, we have not seen any patients with flu like symptoms. So over the past 10 years, not only have we dramatically improved the chemistry but we have also dramatically improved the screening for target sequences for our specific oligos, as demonstrated here, for APOCIII, FXI and TTR.

So as I mentioned before STAT3 is our first drug using the 2.5-technology. 2.5 as compared to 2.0 is approximately 10 times more potent. Patients have good tolerability. This is an example of a patient treated in MD Anderson Hospital in a Phase 1 study. This patient had diffused large B-cell lymphoma, had been refractory to 12 prior therapies, had not obtained a partial response.

We had enrolled three patients with diffused large B-cell lymphoma into this trial. Two of the three have had sustained partial responses. This woman is a 63-year-old woman who failed 12 prior therapies, has remained stable for 11 months now receiving monotherapy, IV administered weekly STAT3 therapy at MD Anderson Hospital.

Isis is partnering our progress. We have made much progress this year in 2012 with partner program at earlier stages in therapeutic areas with higher risk. Examples of that are neuro SMA. When we partnered that program, we were just about to enter the clinic. So we had a drug for SMN that was going to be our first drug administered to children and infants, which at Isis we had never done before. It required intrathecal administration, again which we had not done before. It was a novel target. So we made the decision to partner earlier there given the risk.

Another program that had high risk was cancer. so, although we did see some very interesting partial responses in our Phase 1 program, given the larger cost of developing a drug these days across multiple therapeutic indications for cancer, we made the decision to partner earlier on. So one of the ways we do partnering is, companies take an option to license the drug.

So as I mentioned before, both GSK and Biogen Idec have licensed both TTR amyloidosis as well as SMA with the option to license the drug, which gives us superior downstream economics and allows us to control the earlier stages of development. So far we have generated over $2 billion in cash from these partnerships.

Just very briefly, we are in a very good financial position. We told the street we are going to end this year with over $325 million in cash. Our goals for this year are commercialization at KYNAMRO, positive Phase 2 and 3 data from up to nine programs. We have talked about almost all of these today. Initiation of likely three Phase 3 studies in TTR. SMN will have two. APOCII will have one Phase 3 study. Initiation of four additional Phase 2 studies in both cancer and some of our metabolic targets.

Likely, additional partnering opportunities with a number mature programs. Again, these remain Isis wholly owned, including APOCIII, FXI, CRP, and EIF4E which is a drug being developed for prostate and lung cancer that we haven’t had time to talk about today.

So, in conclusion, Isis has been in a very strong financial position. We have never before had so many drugs in clinical and preclinical development, 28 and our business development activities are keeping us all very busy.

Thank you very much and I look forward to answering any questions in our breakout in the New Yorker Sands room. Thank you very much.

Question-and-Answer Session

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