Executives
Stanley Crooke - CEO and Chairman
Daniel Gaudet - Dept of Medicine, Université de Montréal and Scientific Director of the Genome Quebec Technology Center and Biobank
Richard Geary - SVP of Development
Lynne Parshall - COO
Walter Singleton - CMO
Wade Walke - VP of Corporate Communications and Investor Relations
Analysts
Eric Schmidt – Cowen and Company
Stephen Willey - Stifel, Nicolaus & Company
Jim Birchenough - BMO Capital Markets
Andrew Goldsmith - Canaccord Genuity
Ted Tenthoff - Piper Jaffray & Co.
Isis Pharmaceuticals, Inc. (ISIS) ISIS-APOCIII Rx Phase 2 Monotherapy Data Conference Call September 3, 2013 11:30 AM ET
Operator
Welcome to Isis Pharmaceuticals conference call to discuss ISIS-APOCIII Rx Data. Please note that this event is being recorded. Leading the call today from Isis is Dr. Stan Crooke, Isis Chairman and CEO. Dr. Crooke, please begin.
Stanley Crooke
Good morning everyone and thank you for joining us on today’s webcast. The purpose of the webcast is to discuss the results of an interim analysis of the third set of Phase 2 data on ISIS-APOCIII Rx, our triglyceride-lowering drug. Dr. Daniel Gaudet, a principal investigator in this study presented these data this past week at a PACE meeting session that occurred concurrently with the European Society of Cardiology Congress, in Amsterdam.
Our study is fully enrolled and it is still ongoing and we’re encouraged by the data we’ve observed thus far. The analysis reported this last weekend by Dr. Gaudet at this meeting of physicians in Europe is a midpoint interim analysis with 28 patients who have completed 13 weeks treatment. We will have the full data from this study as well as additional data from our APOCIII Rx program in November at the American Heart Association meeting.
We will also present additional Phase 2 data on ISIS-APOCIII in patients with familial chylomicronemia or FCS on September 21st at the National Lipid Association meeting. So the next good information that you will be getting about APOCIII Rx is actually before the AHA and at the NLA meeting in just a couple of three weeks and that will present the chylomicronemia data, the data in patients with FCS. So we hope that you will join us for all these presentations.
Slide 2, just shows the participants, Lynne Parshall, Chief Operating Officer; Rich Geary, Senior Vice President of Development; Walter Singleton, Chief Medical Officer and Vice President of Development; and Wade Walke, Vice President of Corporate Communications and Investor Relations and our special guest Dr. Daniel Gaudet, Scientific Director of the Genome Quebec Technology Center and Biobank and the principal investigator on this study we are reporting today, all of these people are joining me.
Slide 3, shows the agenda for our webcast. Richard will begin the discussion with a quick introduction of ISIS-APOCIII Rx. Dr. Gaudet will present the data from the Phase 2 study he presented on Saturday. Richard will then discuss the design and the results of our overall Phase 2 program to date and then after that I will close the call by discussing the next steps for ISIS-APOCIII Rx and of course we will it up for questions.
Now Wade will you read our forward-looking language statement please?
Wade Walke
Thank you, Stan. As a reminder to everyone, this webcast includes forward-looking statements regarding the discovery, development, and potential of drugs for cardiovascular diseases, and the development, activity, therapeutic potential and safety of ISIS-APOCIIIRx.
Any statement describing Isis’ goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of ISIS-APOCIII Rx, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs.
Isis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis.
As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2012, and its most recent quarterly report on the Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.
Now I will turn the call over to Richard.
Richard Geary
Thanks, Wade. Today we will present another set of data from the Phase 2 program on our triglyceride-lowering drug ISIS-APOCIII Rx. What we’ve seen from this drug across all the studies to date is remarkably consistent. These data confirm and bolster our earlier observations that one, ISIS-APOCIII Rx is a very effective triglyceride-lowering drug, which shown that it is equally effective in combination with fibrates and as a single agent.
Two, we get comparable reductions of triglyceride irrespective incoming triglyceride levels and this is important because other triglyceride-lowering drugs tend to work less well in patients with severely high triglycerides. Three, we’ve also shown that ISIS-APOCIII Rx has a positive impact on other lipid parameters measured. It raises HDL, lowers other atherogenic lipids such as apoC-III containing VLDL without raising non-HDL.
Four, it has also shown improvements in multiple measures of glucose control and consistent trends toward enhanced insulin sensitivity in patients with high triglycerides and type 2 diabetes. And finally five, in all studies to date the drug has been generally safe and well tolerated.
The most important new observation from the study reported this weekend is that ISIS-APOCIII Rx is showing good efficacy as a single agent in patients with very high to severely high triglycerides. This is an important finding because the initial indications we’re pursuing for this drug are in patients with severely high triglycerides, in other words, triglycerides higher than 880 mg/dL.
In Slide 6, there are approximately a 100,000 patients in the U.S. and Europe, who have severely high triglycerides despite currently available triglyceride-lowering therapies including diet. We believe that ISIS-APOCIII Rx may play a meaningful role in the treatment of these patients who remain at significant risk of cardiovascular disease, pancreatitis and many of whom have other serious comorbidity such as diabetes or metabolic syndrome.
Standard therapies on the market today like fibrates are not able to lower triglyceride sufficiently in these patients to bring them to recommend at triglyceride levels. Because of the lack of truly effective therapies, these patients are very much in need of new treatment options.
apoC-III as a remainder as a genetically validated target is well understood, lower levels of apoC-III are associated with favorable lipid profiles as well as enhanced health and longevity. These data are evident when you look at so called experiments of nature in which due to genetic differences three different well studied human populations have apoC-III levels with their either lower or higher than normal levels.
The first two populations Ashkenazi Jews and Old World Amish have mutations in the apoC-III gene that leads to lower levels of apoC-III. Because of their low apoC-III levels these people experience many favorable health factors such as reduced triglycerides, reduced blood pressure, reduced atherosclerosis and improved insulin sensitivity and a longer life span.
In contrast, a population of Asian Indian men who have apoC-III levels that are higher than normal have high triglycerides and a higher incidence of cardiovascular disease as well as nonalcoholic steatohepatitis liver and insulin resistance.
We believe that ISIS-APOCIII Rx can be used as a single agent or in combination with existing drugs, used to treat patients with high triglycerides. The data we’ve reported this summer, gives us confidence that ISIS-APOCIII Rx could be an effective treatment for patients with severely high triglycerides and supports our enthusiasm for this drug.
Slide 9, summarizes our Phase 2 experience to date. We’ve observed significant reductions of triglycerides in apoC-III with a majority of patients in the 300 mg dose cohorts of each study achieving triglyceride levels below a 150 mg/dL. This is pretty remarkable when you consider that the patients who entered the study we’re reporting today at an average incoming triglyceride level of 660 mg/dL.
We are also very encouraged by the effect by ISIS-APOCIII Rx on the overall lipid profile on these patients. Not only did treatment with ISIS-APOCIII Rx significantly reduce apoC-III in triglycerides, but it substantially raised HDL, the good cholesterol without increasing non-HDL. In these studies we’ve patients with incoming triglycerides ranging from 187 mg/dL to 1,822 mg/dL.
The effects we observed on triglycerides were irrespective of incoming triglyceride levels and we observed consistent reductions in triglycerides in all of these patients. We also observed improved measures of glucose control and consistent trends toward improving insulin sensitivity and patients with high triglycerides in type 2 diabetes and of course we’re very encouraged by the safety and tolerability profile of the drug in these studies, particularly what we’ve observed in our 300 mg dose, the dose we’ve selected as our Phase 3 dose.
And now I’d like to turn the call over to Dr. Gaudet to walk us through the interim monotherapy analysis that he presented this weekend in which have to study participants, about 28 patients -- exactly 28 patients have reached the primary endpoint at 13 weeks.
Dr. Gaudet is the Scientific Director of ECOGENE-21 clinical trial center in Genome Quebec Biobank Technology Center. He is also one of the founders of the Lipid Metabolism Research Clinic, which he has been managing for several years now at Chicoutimi Hospital. He is Associate Professor of Medicine at University of Montreal and has been chair holder of the Canada Research Chair in preventive genetics and community genomics since 2001. Dr. Gaudet has led integrated clinical and research activities in the field of genetics, especially with regard to lipid metabolism disorders and their associated risks for some 20 years.
Over the years he has coordinated some 160 trials and academic projects involving the development of new drugs and technologies. He was an important investigator involved in the development of KYNAMRO and is the lead investigator for both the fibrate combination study and the monotherapy study in patients with high to severely high triglycerides we’re discussing today.
So now I’ll turn the call over to Dr. Gaudet.
Daniel Gaudet
Thank you, Richard. On Slide 11, we see the study designed of the multicenter randomized double-blind placebo controlled study involving 85 patients overall and as Richard said, we’re actually completing the analysis of this study and the interim results will be presented today.
This study was designed to demonstrate that the ISIS-APOCIIIRx can decrease TG and apoC-III levels. It was also evaluating the effect of this medication on overall lipid profile and post-prandial metabolism including TG rich lipoprotein characteristics, [on the micro clearance] and kinetics.
In this study there were two cohorts. The first one was an add-on to fibrate cohort, involving patients with triglyceride levels above 225 and below 2,000 on top of fibrates. This cohort involved 28 patients. The second cohort was in on monotherapy with patients having very high triglyceride levels of up to 440 and again below 2,000. This cohort involved 57 patients. After running period, these patients were randomized on either antisense drug the 100 mg, 200 mg or 300 mg weekly or placebo we treated for 13 weeks and then followed for an additional period of 13 weeks. The efficacy analysis presented today included 28 patients who completed 13 weeks of treatment. Safety data includes all patients exposed to the drug.
On Slide 12, we see here the baseline characteristics for only the patients who were included in the efficacy analysis from the different dose group in the monotherapy cohort. The dose groups overall were reasonably well balanced for all key baseline characteristics. Average triglycerides were very high, which range from [505] to 655 mg/dL with individually high as 1,822 mg/dL sort of range.
On Slide 13, all three doses produced no dependent significant reduction in apoC-III up to 79% in this study, which is consistent with the response were observed in the all of these studies to date. Again, here these are results of interim analysis and the study is still ongoing.
On Slide 14, the treatment with ISIS-APOCIIIRx produced remarkable dose dependent reductions in fasting triglyceride that was statistically significant of all doses with reduction of up to 75%. This is observed in both per percentage and illustrated in the bottom panel in milligrams per deciliter.
Slide 15 shows that the treatments with ISIS-APOCIIIRx also produced remarkable dose dependent increases in HDL cholesterol that was statistically significant for both the 200 and 300 milligram dose cohorts with increase of up to 57% the bottom lined on back of the placebo group.
Slide 16 now. On this slide we see the results for the 300 milligram dose compared to placebo. This comparison shows that the favorable effect of ISIS-APOCIIIRx on multiple lipid parameters. The 300 milligram dose has been selected as the dose that Isis will use in the Phase 3 studies. There were no adverse changes in ApoB and our non-HDL cholesterol.
On Slide 17, this slide shows baseline and of treatment values as well as percent reductions for the key lipid parameters. Note the range of the values, post treatment range in particular almost all patients – not almost, all patients were – there were no non-responders, all patients responded very well with a range between 105 and 152 for triglyceride, which was quite impressive here. Till now there were no non-responders and again we’re presenting interim analysis that is very, very impressive at this point. To reiterate, this large and statistically significant reduction in triglycerides, and after we changed a bit a significant increase in HDL as well on both VLDL cholesterol and HDL cholesterol and total lipid will be -- the efficacy was very, very, very important.
Slide 18, compares the effect of the 300 milligram dose on the key lipid parameters across the different cohorts in the Phase 2 studies. First column illustrates the results obtained in the single agent diabetes. Second column, in the single agent in very high TG and in third column the add-on cohort results. If there is a very important consistency in the reduction obtained in VLDL ApoC-III, total ApoC-III and triglyceride level as well as the increase in the HDL cholesterol in all these studies. There were no adverse change in non-HDL cholesterol and overall again these interim analysis shows pretty consistency -- important consistency across the studies.
On slide 19, in terms of safety, after 12 - 13 weeks of treatment, there were no related serious adverse events or significant adverse events. There were no treatment-related liver enzyme elevations. No abnormalities in the renal function or no clinically meaningful changes in other laboratory values. In term of tolerability there were no flu-like symptoms and very infrequent and predominantly mild injection site reactions. Those two last symptoms or signs are more related to the apoC-III therapy than to the (indiscernible) ApoC-III of the target.
On Slide 20, conclusions from the monotherapy study in patients with high to severely high triglycerides shows dose dependent and significant, rapid and robust durable reductions in triglycerides of approximately 75% and ApoC-III of approximately 79%. The treatment improved overall lipid profile, including the decreased triglycerides, VLDL-ApoCIII, ApoC-III, and the atherogenic lipid particles such as apoB and a -- the non-HDL cholesterol. HDL cholesterol significantly increased and the drug was generally safe and well tolerated in the patients who have been treated till now.
Now let me turn the call over to Richard again.
Richard Geary
Thanks, Dr. Gaudet. I will spend the remainder of the call reviewing the mechanism of apoC-III and then summarizing our Phase 2 experience to date with APOCIII Rx.
First as a reminder, the apoC-III protein is synthesized principally in the liver and upon secretion from the liver is associated with apoB containing atherogenic lipid proteins, VLDL and LDL and also HDL. And when apoC-III is associated with VLDL, it essentially inhibits the movement of triglycerides from VLDL and LDL to HDL. So if you decrease apoC-III, you would expect to both decrease serum triglyceride levels and shift triglycerides from VLDL and LDL to HDL. Both apoC-III and high triglycerides are validated independent risk factors for cardiovascular disease.
The cartoon on Slide 23 illustrates how apoC-III may inhibit the clearance of triglycerides from blood. apoC-III associates with lipid proteins in blood and acts as a brake or suppressor for lipoprotein lipase, the enzyme that causes degradation of triglycerides, illustrated here in the upper left hand side of the slide. The suppression of apoC-III synthesis with ISIS-APOCIII Rx in patients with high triglycerides should improve triglyceride clearance thereby improving peripheral energy supplies and increasing triglycerides as illustrated here in the upper right hand side of the slide.
We’ve conducted two randomized double-blind placebo controlled studies in patients with high triglycerides -- very high triglycerides and severely high triglycerides. We evaluated the effect by ISIS-APOCIII Rx in patients with high triglyceride and type 2 diabetes. We also evaluated the effect of APOCIII Rx both as a single agent and in combination with fibrates.
On slide 25, we have the design of the first study we reported in June at the ADA meeting. This was a randomized double-blind placebo controlled study in patients with high triglycerides and moderate type 2 diabetes in which we compared treatment with placebo to the effects of treatment with 300 milligram per week of APOCIII Rx for 13 weeks.
Slide 26, shows the remarkable effects of ISIS-APOCIII Rx on the overall lipid profile of these patients. Notice that the patients treated with APOCIII Rx achieved an 88% reduction of apoC-III and a 72% reduction of triglycerides. Treatment with the APOCIII Rx also resulted in a 40% increase in HDL or the good cholesterol.
On Slide 27, make the final important observations from this first study relate to insulin sensitivity and diabetes. Treatment with ISIS-APOCIII Rx improved multiple measures of glucose control, including glycated albumin and fructosamine and hemoglobin A1c. We also observed consistent trends toward enhancing insulin sensitivity. This if confirmed represents an important profile enhancement for ISIS-APOCIII Rx because patients with severely high triglycerides, our first indication, are frequently diabetic or prediabetic.
On slide 28, is the design of the second study we conducted on ISIS-APOCIII Rx. This was a randomized double-blind placebo control study with two separate cohorts. The first cohort was in patients with high to severely high triglycerides for 225 to 2,000 milligrams per deciliter despite treatment with fibrates and this cohort was designed to treat patients who were on stable doses of fibrates that will maintain throughout the study for 13 weeks with once either with once weekly placebo or 200 milligram or 300 milligram of ISIS-APOCIII Rx.
The second cohort in this study was the one described today by Dr. Gaudet. These were patients with very high or severely high triglycerides keep treated with APOCIII Rx as a single agent.
Slide 29 shows the results from the APOCIII Rx fibrate combination study. Here we see that in the 300 milligram APOCIII Rx cohort, APOCIII Rx reduced on average apoC-III by 70%, triglycerides by 64% and apoC-III containing VLDL by 77%. It also on average increased HDL by 52%. Importantly there was no significant effect on non-HDL cholesterol even when ISIS-APOCIII Rx was added to fibrates, producing the optimal changes in the lipid profile that these patients need. It lowers atherogenic risk factors and increases good cholesterol.
On Slide 30, which Dr. Gaudet also reviewed, we highlighted the effect of treatment with ISIS-APOCIIIRx on all three patient population studied. In this slide we highlight a 300 mg dose, as this will be the dose we plan to use in our Phase 3 program which we are on track to start early next year.
As you can see in this slide, treatment with ISIS-APOCIIIRx consistently reduces apoC-III, Triglycerides, apoC-III associated VLDL complexes and increases HDL with a positive effect on non-HDL. So I hope you can see from this slide why we are so encouraged with the performance of ISIS-APOCIIIRx and why we have chosen the 300 mg dose to move forward.
Slide 31, summarizes our overall experience with ISIS-APOCIIIRx and its quite remarkable that we observed consistent Triglyceride in apoC-III lowering in across all patient population studied. In all three data sets we observed improvements in the overall lipid profile of these patients including substantial increases in HDL without increases in non-HDL. These results were similar when used as a single agent or in combination with fibrates and similar irrespective of the incoming triglyceride levels of the patients. In fact 86% of the patients treated with 300 mg of APOCIIIRx in a Phase 2 studies to date achieved triglyceride levels less than 150 mg/dL. We also observed positive effects on glucose control and trends toward improved insulin sensitivity.
Slide 32 summarizes the overall safety profile of ISIS-APOCIIIRx across Phase 1 and the three patient population studied to date including all patients enrolled in the ongoing monotherapy cohort. We are very encouraged by the safety profile of the drug today. There have been no drug related elevations of liver enzymes greater than three times the upper limit of normal even when added to stems or fibrates and no clinically meaningful changes in renal function, no clinically meaningful changes in other biochemical or hematological laboratory values. And the drug has been well tolerated.
The most important AE and our most common AE has been in frequent injection side reactions that were predominantly mild in nature. In fact there have been no discontinuations due to ISRs and we also have not observed any flu like symptoms associated with drug treatment. In fact investigator feedback has been quite positive. What Dr. Gaudet has told us that in his experience the local reactions are in general very minor, and for the majority of the patients their experience with ISIS-APOCIIIRx is very positive. This improved tolerability profile we have observed with ISIS-APOCIIIRx is consistent with other newer second generation antisense drugs we have been reporting.
And now I’d like to turn the call back over to Stan.
Stanley Crooke
Thanks Richard. Slide 34, I think all the data from our Phase 2 program that we’ve presented this summer supportably for ISIS-APOCIIIRx is potentially a very attractive commercial asset. ISIS-APOCIIIRx addresses an important unmet medical need in patients with multiple health issues caused in part by high triglycerides. The most important aspect of ISIS-APOCIIIRx in the extend of triglyceride in apoC-III lowering of produces and this is unprecedented. It also has a positive impact on the overall lipid profile significantly raising HDL cholesterol. It may also provide benefit to many of these patients who also have diabetes or are pre-diabetic. Finally it can be used in combination or with existing therapies and that means it doesn’t have to displace any existing therapy to be commercially successful.
We have one more element of the Phase 2 program that we’ll be sharing with you at the National Lipid Association meeting on September 21st. At this meeting we will present Phase 2 data from a study in patients with familial chylomicronemia or FCS. For those of you who don’t know about FCS. FCS is a very rare ultra-orphan genetic disorder. There are about 3000 to 5000 patients worldwide with FCS. So you can think of it very much like almost like SFH, a disease you’ve become much more familiar with. The disease is usually the result of the genetic defect that leads to lipoprotein lipase deficiency and this in turn leads to a decrease in breakdown in clearance of triglycerides from the blood. Lipoprotein lipase is the enzyme that’s inhibited by apoC-III and these patients have very severe disease with triglycerides frequently in excess of 2000 mg/dL. We do look forward to sharing these data with you now I guess in just two -- little more than two weeks.
Then at the end of the year in November at the American Heart Association meeting in Dallas, Rosanne Crooke, the Head of the Cardiovascular Program at Isis in an invited presentation we’ll present more detailed summary an update of the entire Phase 2 experience with this drug. So we hope you’ll join us for those two presentations on ISIS-APOCIIIRx. We’re now working with experts to finalize our Phase 3 plan since we’ve prepared to meet with regulators in the U.S. and EU. Once we have our end of Phase 2 meetings we plan to share more detail about the upcoming Phase 3 programs which we plan to begin early next year. And just as a parting reminder ISIS-APOCIII is a drug that we own. As I mentioned we plan to begin our Phase 3 program for this drug early next year which sets us up for a potential regulatory filing in 2016, 2017 and of course we look forward to keeping you apprised of all the progress that we’re making in this program as well as our other programs.
And with that I’ll bring the conversation to a close and open this up for question. Amy if you can set us up please.
Question-and-Answer Session
Operator
Thank you. (Operator Instructions) Our first question is from Jim Birchenough with BMO Capital Markets. Hello Mr. Birchenough, are you there? Hello Mr. Birchenough have you placed your phone on mute? Our next question is from Eric Smith with Cowen and Company.
Eric Schmidt – Cowen and Company
Thanks for taking my question and thanks for the call today. Maybe for Rich or Stan just trying to get a little bit more insight on your thinking for the Phase 3 program, you have been consistent in saying that you’re going to go after patients above 880 mg/dL triglycerides. I assume that’s on maximum triglyceride lowering background therapy that number?
Stanley Crooke
It will be probably all comers will – as we’ve learned that the vast majority of these patients come in with on no drugs, but we will allow people to be on their maximum tolerated drug and I would -- but I would still expect probably 70% or more of the patients will be on no drug at all.
Eric Schmidt – Cowen and Company
And Stan, did you have such patients above 880 in this trial who were on apoC-III and did they perform just as well as sort of the means?
Stanley Crooke
Yes. We’ve seen no difference in response irrespective of incoming triglyceride or irrespective of whether the patients are on a fibrate lowering drug. Now in this monotherapy study of course we didn’t allow anybody to be kicking any drugs, but you recall we reported on the fibrate data earlier.
Eric Schmidt – Cowen and Company
Okay. So you know you don’t have a lot of patients above 880, it would seem you’re still comfortable going right into a Phase 3 from a safety efficacy standpoint in that population?
Stanley Crooke
Absolutely. We have -- if you have a look at the – if you were to for example look at a dot plot of percent reduction or absolute reduction of triglycerides is a function of incoming triglycerides just linear or next close to linear as you would expect. And so we’re very, very, very confident at levels up to 2000. We see a very significant reduction’s that are consistent with the numbers that we’ve just shown here.
Eric Schmidt – Cowen and Company
Okay. And there wouldn’t be any FDA requirement first time or greater sample size, of patients in that range in Phase 2?
Stanley Crooke
Well I won't speak for the FDA until we go talk to them, we don’t believe so.
Eric Schmidt – Cowen and Company
And what's your latest thinking on how many patients you’ll need to treat at greater than 880 to get approval?
Stanley Crooke
Richard, maybe you can respond to that.
Richard Geary
Yeah, I think the thought and it's consistent with the advice that we’ve gotten in Europe about a year ago is that a study of about 100 patients that are randomized and to control and active treatment treated over a year is probably what's going to be needed and then all of those patients would be going into open label, and that’s consistent with the advice we received from EEU and we’ll be presenting that to the FDA.
Eric Schmidt – Cowen and Company
Okay, but that would also …
Stanley Crooke
We’ve been told about safety database is pretty much what you would expect for a population in the 50,000 range in each area and of course that’s all focused on the 880. We’re not commenting today on this ultra rare orphan disease the FCS patients, that would be a different matter altogether.
Eric Schmidt – Cowen and Company
So FCS would not be included in the Phase 3. Do you exclude them or just not now?
Stanley Crooke
No, I mean that the number required for an FCS indication would be dramatically smaller.
Eric Schmidt – Cowen and Company
Right; and would you exclude those patients from the Phase 3 or might they show up and just not be detected?
Stanley Crooke
What I would rather do is delay commenting on that until the 21st. We will be reporting Phase 2 data on patients with FCS on the 21st of September and at that point then we can begin to discuss that indication in more detail, all right.
Eric Schmidt – Cowen and Company
Okay. Thanks for answering all my questions.
Stanley Crooke
Good luck.
Operator
The next question is from Stephen Willey with Stifel. Go ahead please.
Stephen Willey - Stifel, Nicolaus & Company
Yeah, thanks for taking the question. Stan and Richard, I guess when I look at the KYNAMRO data it looks like you get about 75% to 80% of your maximal reduction in LDL occurring within the first 12 weeks and there’s still quite a bit of additional benefit beyond 12 weeks and so. Should we be thinking about this in the same context; is that -- are those kinetics that are specific to the lowering of LDL or are they specific to the distribution kinetics of the chemistry within the target issues?
Stanley Crooke
They are tied almost directly to the elimination half life of APOCIIIRx is a little shorter than KYNAMRO but we don’t believe in 13 weeks we have achieved the maximum reduction that would be obtained at steady state. So, the short answer is, you should probably expect behavior that’s similar not equal but similar of what you saw with KYNAMRO. Richard, do you want to amplify on that?
Richard Geary
No, I think that’s exactly right. It looks like we’re getting really robust effects in 13 weeks and when you go beyond 13 weeks to six months I think you can expect with these long half life drugs that you would get even more.
Stephen Willey - Stifel, Nicolaus & Company
Okay. And then can you provide any color around whether or not, I know the changes here were small in terms of the LDL increases, but were they also dose dependant. I think we have just a 300 mg data in terms of LDL?
Stanley Crooke
Not precisely dose dependant, but the challenge here is not a bit statistical, and so we have a difficult time knowing how to interpret the LDL. And what our advisors tell us is to report on non-HDL which is more consistent and more important.
Stephen Willey - Stifel, Nicolaus & Company
Okay.
Richard Geary
And for non-HDL and for apoB there is dose dependants, in the LDL it's too easy.
Stephen Willey - Stifel, Nicolaus & Company
Okay. Thanks.
Stanley Crooke
I think one of the remarkable things that we’ve observed in the patients who come in with the super high triglycerides almost all of them are getting to below 150, and they’re getting to below 150 without any other drug. So, if you have a triglyceride disease, if you have a triglyceride disease, getting your triglyceride as low as possible so that you can eat a normal diet and not worry about it and live a normal life I think will be very important to people.
Operator
The next question is from Jim Birchenough with BMO Capital Markets. Go ahead please.
Jim Birchenough - BMO Capital Markets
Hi guys congrats on the data, I had a few questions, just on getting to below 150 sten what was the highest baseline that was able to get below that level, you know did the 18, 20 patient get below 150?
Stanley Crooke
I can’t remember which patient that is, but of the -- we have now five patients who have competed in the 300 mg cohort all five were 150 or below. And the highest level in that group ratio was what?
Richard Geary
702, that’s down to – below to 150.
Jim Birchenough - BMO Capital Markets
Below 150. And I know you want to save the FCS discussion for September 21st, but maybe when you talk about a global market of 3000 or 5000 patients, how many patients are identified in the U.S. and is there some prospect for you guys retaining rights for the orphan or ultra-orphan indication?
Stanley Crooke
Richard, who don’t you respond to the first and then I’ll take the second.
Richard Geary
Okay. I apologize I heard that last half of the question, I didn’t hear the first.
Jim Birchenough - BMO Capital Markets
Yeah, just in the U.S. what's the number of patients who have been identified with FCS and what – how are they treated currently? Is it apheresis or something else and then for Stan it was really, is this something, is ultra-orphan indication something you can hang on to yourselves?
Richard Geary
Yeah, so first of all the identified numbers in the U.S. are really identified through the lipid centers here in the U.S, these are patients that are sick enough that they’re being treated in specialty centers, so they are known and the estimates are anywhere – are very similar to the HoFH, somewhere in the 1 to 3000 numbers, very low numbers overall. And because these patients have such high triglycerides they are seen in the lipid clinics often because they’re coming into the hospital with pancreatitis often acute pancreatitis on a regular basis. So that’s the situation with and the numbers.
Stanley Crooke
And with regard to current treatment there really isn’t anything but apheresis. You’ll remember that Novartis has a 30 patient Phase 3 study, I think it's 30 patients, Phase 3 study on a drug called DGAT1 that reduces chylomicron absorption, produces diarrhea as a -- I think it's principle side effect. So that gives you a sense of the size of the patient population and the size of the FDA requirements for a Phase 3 program in FCS. And we are as we said with regard to partnering and Lynne can amplify on this. We have already overwhelming interest in this drug as the fellows who’ve been at the ESC kind of test.
But we're not willing to partner today we plan to do a good bit of the Phase 3 obviously somebody comes in and makes a preemptive offer where the dollars look right we’d certainly consider it, but that’s not our plan today. It is not our plan to commercialize the FCS indication ourselves but to make that a part of the package that we license.
You’ll remember that a simple minded view of the rolls of apoC-III on lipid would argue that an APOCIIIRx agent that is an agent that reduces apoC-III would be very unlikely to work in patients with FCS because these are people who have none of the enzymes that apoC-III is thought to prevent from working. Nevertheless there’s been a lot of discussion over the last few years about other things that apoC-III might do, so we decided to go ahead and study in these patients. And as I say, we’ll be reporting those data on September 21st and I’ll withhold further comments on those data of these patients until then Jim. Lynne, do you want to add anything to our partnering or anything?
Lynne Parshall
No, I just would reiterate that the fact that there is a tremendous amount of interest in this drug and I think the data justify that.
Jim Birchenough - BMO Capital Markets
And just a quick final question Stan, with KYNAMRO we saw patients that had the most rapid and profound reductions in LDL being the patients where you might see things like fatty liver; is there anything remarkable about patients that have massive reductions from 720 to less than 150 in terms of anything particular to their side effect profile or it doesn’t look pretty much the same no matter how rapid and profound the reduction is?
Stanley Crooke
I think what's remarkable is there is no safety issue that we’ve identified to date. Remember that the liver side effect’s were tied to a rapid reduction of apoB-100 and it was a -- has been a rapid change in lipid distribution in the liver. So to date we have seen no -- we see elevations that are drug related and so there is no effect. And there certainly is no increase in propensity toward ALT elevations as a function of incoming triglycerides or the rate of extent of reduction of triglycerides to date.
Jim Birchenough - BMO Capital Markets
Thanks, Stan.
Operator
(Operator Instructions) And our next question is from Salveen Richter with Canaccord. Go ahead please.
Andrew Goldsmith - Canaccord Genuity
Hi, this is Andrew Goldsmith on the line for Salveen. Congratulations on the nice data. Just looking between trials to my kind of untrained eye it looks like maybe the monotherapy trial gave slightly better results than the fibrate trial. Is there anything real there or is that just kind of a low ends that work?
Stanley Crooke
Oh my goodness no. I mean to have totally different sets of investigators, trials, patients and end up with a 70% versus 79% reduction is astonishingly consistent. So we look at those data and we can see no evidence that there is any difference as a function of incoming triglyceride whether you’re on fibrates or not, essentially we get the same response in everyone who walks in the door.
Andrew Goldsmith - Canaccord Genuity
Okay, great.
Stanley Crooke
The short answer to your question is those are not – those are numbers that are so close together that it really surprises me to see that level of consistency and if are we doing two single agent study and saw a 79% and 70% reductions and they were two separate studies, I wonder how in the world we got those consistency, so no there’s no difference. Richard, do you want to add anything to that?
Richard Geary
No, that’s exactly right. Consistency is amazing.
Andrew Goldsmith - Canaccord Genuity
And you feel the same way about HDL and the LDL and all the parameters there, they are all basically the same?
Stanley Crooke
Yeah, I think there is obviously dose dependence in the HDL effect just as there is in the apoC-III and triglycerides. But if you look across the board, is there a difference between 40% and 48% and 54%, I can’t imagine it. So if you look at the 300 mg dose which is the Phase 3 dose, I think one of the very comforting things to me as the drug developer is how absolutely consistent the efficacy is and the fact to date they have no non responders.
Andrew Goldsmith - Canaccord Genuity
Great. And then maybe thinking about the kinetics of it, it looks like now the last injection week 13 and you still have kind of maintenance of efficacy about 40 days later, is that returned to the Phase 3 trial or you’re still going to want kind of the weekly dosing?
Stanley Crooke
We’ll do weekly dosing. We think that’s the best with these drugs and it's consistent, remember all these drugs behave very similarly. All of the second generation antisense drugs have elimination half life that were about two to four weeks. So you can just assume that the kinetics of the behavior of response will be very similar. And what that means obviously is that after you stop dosing at 13 weeks you probably should and we always do see a continuing decrease for another week or two because you haven't gotten to steady state there. And after dosing terminates, you have benefited probably, you last for two to three months or longer.
Andrew Goldsmith - Canaccord Genuity
Great. And then maybe just the last question for Dr. Gaudet, the lack of non responders is really quite striking, can you conceptualize any kind of patient population that you might expect to non respond or is this just – it should work in everyone?
Daniel Gaudet
Well at this point as Stan said and as you have seen on the slides presented there were no non responders, over time with additional data on more patient we’ll see (indiscernible) but at this point, it will, obviously triglyceride in heterogeneous population or different diseases, different pathways, different risk associated with high TG. So over time we will see but till now, I’ll tell you that I am quite impressed by the fact that there were no non responders and a huge decrease in TG.
Stanley Crooke
Probably the answer you would have gotten two years ago or a year ago or six months ago which is still a valid answer I suspect is the patients with FCS would be expected not to respond or not to respond nearly as well to APOCIIIRx than other patients. But as I say we’ll show you what we’re getting in those patients on the 21st and then you can make your mind up.
Andrew Goldsmith - Canaccord Genuity
Thanks so much.
Operator
The next question is from Ted Tenthoff with Piper Jaffray. Go ahead please.
Ted Tenthoff - Piper Jaffray & Co.
Great, thank you very much, and congrats on very impressive data. Digging little bit more into the Phase 3 side if I may, you described the injection by reactions as infrequent and mild; can you give us a little bit more color around that?
Stanley Crooke
Well we have done it as well as we can, I think Dr. Gaudet’s quote probably does the best Ted which is that the patients actually get along with the drug very well, and there’s a night and day difference between the injection side reactions with KYNAMRO and APOCIIIRx and as I said repeatedly I think we did the drug at the surplus I think we have exaggerated the injection side reactions with KYNAMRO.
Ted Tenthoff - Piper Jaffray & Co.
What do you think the difference is between…
Stanley Crooke
I can’t add any more than what I have talked about for the last four or five calls, we continue to advance our screening. And as a consequence we're with the same chemistry, same design. We’re getting anywhere from – well we’re just about doubling potency when you look at it roughly. Certainly 70% increase in potency and we imposed a new screen that we think is working and helping us reed out those molecules, those sequences that are a little bit prone to produce overall injection side reactions. But again I want to emphasize that KYNAMRO injection side reactions are absolutely no worse than AMRO, I think what really happened with KYNAMRO is that this was the first subcutaneous drug used by most of the physicians in the trials and we should have spent more time educating them on what to expect from a subcutaneous drug. So yeah, I think apoC-III is performing better in all ways than KYNAMRO in terms of injection side reactions, flu like syndromes and so on and those problems with KYNAMRO were exaggerated.
Ted Tenthoff - Piper Jaffray & Co.
Okay, thanks.
Daniel Gaudet
Well, Stan if I can add something on that, based on what my experience with the [mipomersen] and (indiscernible) right at the beginning before we started the clinical trials I was expecting higher incidents of local reaction due to the fact that patients with high triglyceridemia in general have adipose tissue, which is more (indiscernible). But what’s well served in the field is that the incidents of local injection side was as a matter of fact lower that’s what we have observed with [mipomersen] in our clinical trials. At this moment obviously we're still -- we’re still looking at data on this drug in small number of individuals but we’re certainly not dealing with higher prevalence or incidence of local reactions (indiscernible).
Ted Tenthoff - Piper Jaffray & Co.
Okay. That’s helpful, thanks.
Stanley Crooke
Any other questions please.
Operator
There are no further questions in the queue. So this concludes our question-and-answer session. I would like to turn the conference back over to Dr. Crooke for any closing remarks.
Stanley Crooke
Well, thank you very much everyone. We are tremendously excited about our lipid franchise. We are excited about KYNAMRO and its potential. We think APOCIIIRx is going to be an important drug to reduce triglycerides. We are quite excited about our apoA inhibitor that we’ll be reporting data in November, and behind that other drugs that are coming and we’ll be talking to you about in the near term. We think this lipid franchise that we have created is unique in the industry and of unique potential value. With apoC-III and its follow-on being sort of the at the head of the line today. And as I say, we will report additional data on apoC-III on the 21st and then more data on apoC-III at the AHA and then we’ll introduce you to another member of the lipid disorder family of drugs and that’s our APOARx drug where we’ll report first clinical data on that at the AHA. So we have an exciting fall and winter coming in our cardiovascular and other pipelines and we look forward to sharing with you. Thanks very much.
Operator
The conference is now concluded. Thank you for attending today’s presentation. Please disconnect your lines.
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