WEBVTT
00:00:06.959 --> 00:00:08.080
Hello everyone.
00:00:08.320 --> 00:00:15.359
Thank you for joining this latest episode of Lipid Insights Podcast from the National Lipid Association.
00:00:15.599 --> 00:00:16.800
I'm your host, Dr.
00:00:16.879 --> 00:00:17.519
Peter H.
00:00:17.760 --> 00:00:32.399
Jones, and I'm very fortunate today to be uh discussing some new information that was uh released at the European Society of Cardiology 2026 in Munich a few days ago.
00:00:32.640 --> 00:00:40.240
And I'm also very happy to have as my discussant uh today, Dr.
00:00:40.399 --> 00:00:41.280
Christy M.
00:00:41.520 --> 00:00:42.399
Ballantine.
00:00:43.359 --> 00:00:45.039
Christy, welcome.
00:00:45.759 --> 00:00:46.799
Thanks, Peter.
00:00:47.359 --> 00:00:56.079
Listen, now Christy and I uh uh practice together at Baylor College of Medicine for at least 35 years, and so we know each other very well.
00:00:56.479 --> 00:01:06.480
And Christy is currently the um uh chief of cardiology at uh uh Baylor College of Medicine.
00:01:06.560 --> 00:01:11.120
He's also chief of the cardiovascular research at Baylor College of Medicine.
00:01:11.359 --> 00:01:19.040
He's also the director of the cardiometabolic and prevention center at uh at Baylor as well.
00:01:19.359 --> 00:01:27.760
Plus, he's a past president of the National Lipid Association, so he's well well versed in uh in doing these things for the NLA.
00:01:28.480 --> 00:01:36.879
So uh Christy, let's let's get to uh what uh was presented, and you were part of this uh there in Munich.
00:01:37.280 --> 00:01:58.000
Um this is about Plovasserin, which is a small interfering RNA that inhibits Apo C3, and it is a few studies of Shasta 3 and Shasta 4 that are using Plozasterin in patients with severe hypertriglyceridemia.
00:01:58.159 --> 00:02:06.079
These are not FCS patients, these are just the severe hypertriglyceridemic patients that many of us see in our in our clinics.
00:02:06.319 --> 00:02:11.759
So, Christy, if you can uh sort of start us off with you know what are the objectives of these studies?
00:02:11.919 --> 00:02:15.680
What were the entry criteria and the baseline characteristics?
00:02:17.039 --> 00:02:27.919
Peter, uh you know that by definition, we classify severe hyperclostemia as uh greater than or equal to 500 milligrams per deciliter.
00:02:28.639 --> 00:02:33.360
Now, chylomicronemia is what we always think of, that's the worst situation.
00:02:33.439 --> 00:02:37.039
And you know, in the United States we've talked about that as a thousand milligrams.
00:02:37.280 --> 00:02:42.000
In Europe, they do 10 millimoles, which would be 880 uh milligrams.
00:02:42.319 --> 00:02:44.639
But that's when you have childomicrons.
00:02:45.520 --> 00:02:53.360
It's important to also understand is the people who go into these studies, they just don't have a single episode of over 500.
00:02:53.439 --> 00:02:59.039
That they they get into the trial because they have persistent, severe hyperstruxinemia.
00:02:59.120 --> 00:03:11.360
And you you and I know that a lot of times you if you just you know, secondary factors, lifestyle diet, put them on a fibrate omega-3, you will get most of the people down below 500.
00:03:11.520 --> 00:03:14.319
But there are other tough ones who you can't.
00:03:14.400 --> 00:03:17.840
Uh, and sometimes it's genetic factors, polygenic.
00:03:18.639 --> 00:03:25.520
For example, the baseline characteristics here, uh, you had about half of the people with diabetes.
00:03:26.080 --> 00:03:27.759
BMIs 3031.
00:03:27.840 --> 00:03:44.560
So that's a typical scenario we're we're seeing is you know, uh 25% anti cardiovascular disease, but uh the the metabolic syndrome patient who has insulin resistance or diabetes, and really tough to control the triglycerides in these people.
00:03:45.120 --> 00:03:52.879
Uh you had there was uh 7.6 millimoles was the median triglyceride, and that's you know, around 700.
00:03:52.960 --> 00:03:55.680
So that's a that's a high median level of triglycerides.
00:03:56.000 --> 00:04:01.280
One of the things that comes in the study, about 20% had a history of pancreatitis.
00:04:01.520 --> 00:04:03.919
So that's a very important factor.
00:04:04.000 --> 00:04:13.439
Uh is the most severe complication that we're worried about for people with you know these persistent elevations is they get pancreatitis with it.
00:04:13.759 --> 00:04:30.639
So it's a I think an important clinical group, uh severely labeled triglyceritis, mean age was about 50, lots of people with diabetes, a bunch of people with cardiac disease, and also a bunch of them who had had pancreatitis uh in the past.
00:04:31.040 --> 00:04:33.680
So they didn't have to have pancreatitis to get in.
00:04:34.319 --> 00:04:34.879
Right.
00:04:36.319 --> 00:04:42.000
No, about 20% of them had had a history of pancreatitis, so it did not require a history of pancreatitis.
00:04:42.399 --> 00:04:49.839
So the objective of the study was just to look at what cosascerin did on triglycerides alone or anything else?
00:04:50.319 --> 00:04:54.319
Well, that's the primary endpoint was looking at the reductions in triglycerides.
00:04:54.720 --> 00:04:57.279
Of course, they want to see that they lower ApocryI.
00:04:57.360 --> 00:05:08.879
That's uh the way the drug works is you know, blocks the the uh step of going from messenger RNA to protein by degrading the the the messenger RNA to ApoC3.
00:05:09.199 --> 00:05:13.040
Apoc three went down a lot of triglycerides went down 80 percent.
00:05:13.199 --> 00:05:19.600
Now the placebo group went down some too, and that's what we see sometimes when people with high triglycerides get in a trial and get seen a lot.
00:05:19.680 --> 00:05:23.199
You tend to see the triglycerides going down uh with it.
00:05:23.360 --> 00:05:28.879
Uh so and and and if you had colomicronemia, they went down about 85%.
00:05:29.279 --> 00:05:34.800
So if you looked at getting below 500, it's like 91% of the people got below 500.
00:05:34.959 --> 00:05:36.480
A lot of them got below 150.
00:05:36.560 --> 00:05:46.160
So very big differences compared to the placebo group in regards to triglycerides reduction, and in a group that's been tough to treat.
00:05:46.319 --> 00:05:47.600
So that's the first part.
00:05:47.759 --> 00:06:07.600
But I thought I think the part that was the the most impressive overall is that there was a reduction highly significant in pancreatitis, uh 0.22, so is that 78% reduction uh in pancreatitis, the NNT was 24, 4.1 percent absolute risk reduction.
00:06:08.319 --> 00:06:24.480
So uh that's encouraging what was really pretty spectacular was if you'd had a prior episode of pancreatitis, then the the it was the you know, like a ninety one percent reduction, the NNT was three.
00:06:25.519 --> 00:06:31.439
I mean, so you know, that that's so that's I think something that's you know really exciting.
00:06:31.519 --> 00:06:47.279
And and the people who had colomicronemia who came in, uh, you know, they didn't have any episodes of pancreatitis, but so but it it was interesting, you know, some of the people came in over 500 with a past history of pancreatitis, there was benefit there.
00:06:47.439 --> 00:06:58.800
Uh so it's not just and you know, as you know, you and I have known, Peter, that you have somebody and you see when they're at 650 or 700, that's after a long fast.
00:06:59.519 --> 00:07:05.519
And you know, we we've seen, you know, we did the post-perennial studies back in the day with the Patch Brothers and Henry Power and all them.
00:07:05.920 --> 00:07:09.920
You know, that's the best they're gonna be all day.
00:07:10.800 --> 00:07:24.160
And they go to the have a big weekend on the town and have some Mexican food in Cervesas and margaritas, that 650 or 700, if they have a bad weekend, it could be three or four thousand, you know.
00:07:24.240 --> 00:07:27.199
I mean, we we you know, and then they end up in the hospital with pancreatitis.
00:07:27.279 --> 00:07:35.439
So you know, the the person to me, one of the big take-homes is just as you said, uh, you know, with the with this is not FCS.
00:07:36.160 --> 00:07:43.279
This is severe h elevations of triglycerides, including that group that's 500 to 880 uh with it.
00:07:43.360 --> 00:07:52.560
But uh, you know, one of the things is you know, I just this issue of uh pancreatitis, uh you know, and with we get it with heart attacks.
00:07:52.639 --> 00:07:55.279
If someone's had a heart attack, we know you got a lower LDL.
00:07:55.920 --> 00:08:09.199
Uh this the the data's you know, the in the pre previous trial uh with uh uh you know the the ASO also looked very good uh uh with in terms of reducing you know uh pancreatitis.
00:08:09.279 --> 00:08:18.399
So we've got two therapies, these RNA targeting therapies showing the tremendous benefit in these uh individuals.
00:08:18.879 --> 00:08:32.080
Yeah, I mean I I know that the plazasterone and which is the s irna and olizarsin, which is the antisense, the apple C3, they're already approved for the rare condition of familial color micronemia, right?
00:08:32.559 --> 00:08:33.279
Correct.
00:08:33.600 --> 00:08:34.080
Correct.
00:08:34.159 --> 00:08:42.799
And so and then uh and then olezarcin was recently approved for severe hypertrozoidemia.
00:08:42.960 --> 00:08:48.720
So this data will be submitted to the FDA for Plozasserin uh for the same indication.
00:08:48.879 --> 00:08:53.600
But you know, the it it's a it's really nice to see, you mean you this has been a struggle.
00:08:53.759 --> 00:09:02.559
We waited a long time to be able to treat FCS, but as you pointed out, we mentioned it, most of the patients don't have pure FCS.
00:09:02.960 --> 00:09:16.960
And I don't even like the name, you know, FCS versus MCS multifactorial, because the person who doesn't who can the person who comes in there, triglycerides keep running 1500, 2000.
00:09:17.200 --> 00:09:20.399
Well, most of us could never get there no matter what we ate.
00:09:21.200 --> 00:09:27.039
They usually have something genetic, you know, and familial colomicrone syndrome.
00:09:27.120 --> 00:09:38.159
And if you're if you have a pathogenic variant LPL and you get a bad polygenic risk score and some genes for diabetes, well, that's familial, as far as I'm concerned.
00:09:38.399 --> 00:09:44.159
I mean, that person is, you know, I don't know why they shouldn't get the medication because they're not the rare biolic.
00:09:44.399 --> 00:09:52.799
And so this is really good news, I think, for these tough-to-treat patients that we have uh uh, you know, the data that the therapy works.
00:09:53.120 --> 00:10:00.399
Yeah, I mean, I think this is this is wonderful because they, you know, they they struggle to take fibrates, they struggle to take high dose omega-3 fatty acids.
00:10:00.480 --> 00:10:07.600
And even with those, sometimes we can't keep people fluctuating above 500 and more with food they eat and a variety of things.
00:10:07.759 --> 00:10:21.519
So having these drugs available is going to be fantastic in in reducing their risk of uh particularly pancreatitis, which I think can be you know think it, a fatal disease when they um when they have it.
00:10:21.679 --> 00:10:28.399
So well, I guess the the the question is this is a the study with shaft of three and four was a single dose, right?
00:10:28.480 --> 00:10:30.799
It was 25 milligrams given every three months.
00:10:31.440 --> 00:10:33.120
25 milligrams every three months.
00:10:33.200 --> 00:10:33.840
That's correct.
00:10:34.240 --> 00:10:36.480
And it was two to one randomization.
00:10:36.720 --> 00:10:40.879
So, you know, the study's uh one 200 to 100 and about 300 to 150.
00:10:40.960 --> 00:10:47.120
So good two good size studies, uh very similar results, reassuring safety looked good.
00:10:47.200 --> 00:10:53.519
The glucose, you know, there can be some increase, but if you look during the duration of the studies, glucose was maintained.
00:10:53.600 --> 00:11:02.159
You can usually modify something in the therapies to get that that well controlled, and that weren't really seeing any other uh problems besides that.
00:11:02.240 --> 00:11:05.759
There was a hepatic fat small substudy, didn't see anything there.
00:11:05.919 --> 00:11:09.519
So uh overall uh looked look to be uh safe.
00:11:09.840 --> 00:11:14.720
You get an occasional injection site reactions, but those are usually mild and self-limiting.
00:11:14.960 --> 00:11:20.639
Yeah, how many how many of the patients actually got down to a level of normal triangles or less than 150 in these trials?
00:11:20.799 --> 00:11:21.519
Were there any?
00:11:21.919 --> 00:11:24.159
So it oh yeah, there were a lot.
00:11:24.320 --> 00:11:30.639
I mean, you know the uh uh you you had 90 percent getting under uh uh 500, 91%.
00:11:31.279 --> 00:11:35.360
And I forgot the exact number, but I think it's about uh 25, 30 percent.
00:11:35.440 --> 00:11:36.960
I mean, the odds ratio was 12.
00:11:37.279 --> 00:11:44.080
If you got the you were 12 times more likely if you got treated to get there than if you got a placebo, but you know, getting under 150, that's a that's a challenge.
00:11:44.159 --> 00:11:45.600
But it was quite a few people got there.
00:11:45.679 --> 00:11:48.320
It's so you know, really robust reductions.
00:11:48.399 --> 00:11:53.600
Uh, you know, and people in the trials and you see them a little more often, they they tend to do quite well.
00:11:53.679 --> 00:12:01.039
But I think one of the nice things is something that lasts every three months, it it's the therapy still has benefits up to six months.
00:12:01.120 --> 00:12:04.879
So if someone's a little late, you know, it's not gonna all wear off, which is nice.
00:12:04.960 --> 00:12:11.519
As you know, one of the reasons these people are hard to treat is some of them they they have a hard time being compliant with everything.
00:12:11.600 --> 00:12:15.200
It's because it's you they got to be strict on the diet, the exercise, taking the medications.
00:12:15.279 --> 00:12:20.720
So having something that has some durability is it it's nice to get a little safety margin there.
00:12:21.039 --> 00:12:24.480
Yeah, you know, one of the one of the final things I want to uh talk about.
00:12:24.639 --> 00:12:34.799
We've struggled over three decades trying to come up with a a therapy that we could prove that lowering triglycerides and triglyceride-rich lipoproteins can reduce cardiovascular disease.
00:12:35.039 --> 00:12:38.240
Do you think that there will ever be a cardiovascular outcomes problem?
00:12:39.759 --> 00:12:45.360
Or oasarcin to to try to prove that we can reduce cardiovascular events?
00:12:45.759 --> 00:12:56.080
You know, I I thought we had one that was gonna start in uh that there were a couple of them, uh, but uh uh you right now no one's pulled the trigger on these things, Peter.
00:12:56.159 --> 00:12:57.919
So we'll have to we'll have to see.
00:12:58.080 --> 00:12:59.360
I certainly hope so.
00:12:59.440 --> 00:13:02.960
Uh it's a very important studies.
00:13:03.039 --> 00:13:11.200
Uh that there was going to be one comparing uh Apo C3 SRNA to the NHB TL3 along with Oplus C, but that would have been an incredible trial.
00:13:11.279 --> 00:13:12.879
But it would have been very big and costly.
00:13:12.960 --> 00:13:20.799
So I understand sometimes the the companies, you know, have a they it's a lot, there's a lot of risk in there.
00:13:21.279 --> 00:13:22.639
Yeah, there is one thing we need to.
00:13:23.679 --> 00:13:25.200
We do need the study.
00:13:25.519 --> 00:13:32.240
Well, I know we we already know that uh genetically, if you're if you're loss of function, APO C3, you have a low risk of cardiovascular disease.
00:13:32.320 --> 00:13:44.000
So yeah, here we've got drugs that uh can can knock that out, so it should give you over time a reduction in cardiovascular disease in some of these high-risk patients, like you had in the SHAs to three and shaft to four study.
00:13:44.159 --> 00:13:45.279
Yep, yeah.
00:13:45.919 --> 00:13:50.320
So, well, this is any any other final comments about do you think this is enough?
00:13:50.799 --> 00:13:52.399
No, it's it's too much.
00:13:52.559 --> 00:13:53.679
I think it's exciting.
00:13:53.759 --> 00:13:59.759
Uh yeah, you know, I it looks to me that the the the study hit the objectives.
00:13:59.840 --> 00:14:06.639
I mean, that's what the decision for the FDA, but everything looks quite good from uh the data that's been presented.
00:14:06.799 --> 00:14:11.600
Uh the manuscript will be coming out soon uh with it.
00:14:11.759 --> 00:14:14.879
And so uh, you know, I think it all looks really promising.
00:14:15.120 --> 00:14:17.519
It looks it'd be similar to what we have.
00:14:17.600 --> 00:14:26.240
We have there'll be two agents, which is always also nice because get into a little bit of a price war there, uh, and also tends to make it easier for our patients to get something.
00:14:26.399 --> 00:14:29.200
But uh it looked very impressive.
00:14:29.279 --> 00:14:31.679
And the one thing was this NT of three.
00:14:32.000 --> 00:14:40.960
I think one take-home is if someone has had pancreatitis, they're at a high risk for getting it again, and they don't have to be over a thousand.
00:14:41.039 --> 00:14:47.919
If if they're running consistently over 500, that's a high-risk individual who certainly will benefit from treatment.
00:14:48.240 --> 00:14:48.799
Absolutely.
00:14:48.879 --> 00:14:51.120
So you said the the data will be published soon.
00:14:51.200 --> 00:14:54.559
Do you know where the Shasta 3 and 4 will be published?
00:14:55.840 --> 00:15:00.240
I do know where, but I'm not sure if if it's if it's supposed to be public information yet.
00:15:00.320 --> 00:15:02.639
So, anyways, it should it should be soon.
00:15:03.200 --> 00:15:05.120
Okay, okay, that sounds fantastic.
00:15:06.000 --> 00:15:07.120
It's a very good journal.
00:15:07.360 --> 00:15:08.639
Yeah, okay.
00:15:08.960 --> 00:15:20.480
Well, listen, Christy, I know uh you're still over there in Europe, and I appreciate you taking the time to to uh do this uh late breaking uh uh lipid uh insight podcast with me.
00:15:20.559 --> 00:15:24.639
I really appreciate it, and thank you so much for for taking that time.
00:15:24.720 --> 00:15:30.639
And I want to thank everybody else for uh taking the time to listen to this uh uh breaking data.
00:15:30.799 --> 00:15:31.200
Thank you.
00:15:31.519 --> 00:15:32.639
Always a pleasure, Peter.
00:15:32.720 --> 00:15:33.519
Thanks.
00:00:06.959 --> 00:00:08.080
Hello everyone.
00:00:08.320 --> 00:00:15.359
Thank you for joining this latest episode of Lipid Insights Podcast from the National Lipid Association.
00:00:15.599 --> 00:00:16.800
I'm your host, Dr.
00:00:16.879 --> 00:00:17.519
Peter H.
00:00:17.760 --> 00:00:32.399
Jones, and I'm very fortunate today to be uh discussing some new information that was uh released at the European Society of Cardiology 2026 in Munich a few days ago.
00:00:32.640 --> 00:00:40.240
And I'm also very happy to have as my discussant uh today, Dr.
00:00:40.399 --> 00:00:41.280
Christy M.
00:00:41.520 --> 00:00:42.399
Ballantine.
00:00:43.359 --> 00:00:45.039
Christy, welcome.
00:00:45.759 --> 00:00:46.799
Thanks, Peter.
00:00:47.359 --> 00:00:56.079
Listen, now Christy and I uh uh practice together at Baylor College of Medicine for at least 35 years, and so we know each other very well.
00:00:56.479 --> 00:01:06.480
And Christy is currently the um uh chief of cardiology at uh uh Baylor College of Medicine.
00:01:06.560 --> 00:01:11.120
He's also chief of the cardiovascular research at Baylor College of Medicine.
00:01:11.359 --> 00:01:19.040
He's also the director of the cardiometabolic and prevention center at uh at Baylor as well.
00:01:19.359 --> 00:01:27.760
Plus, he's a past president of the National Lipid Association, so he's well well versed in uh in doing these things for the NLA.
00:01:28.480 --> 00:01:36.879
So uh Christy, let's let's get to uh what uh was presented, and you were part of this uh there in Munich.
00:01:37.280 --> 00:01:58.000
Um this is about Plovasserin, which is a small interfering RNA that inhibits Apo C3, and it is a few studies of Shasta 3 and Shasta 4 that are using Plozasterin in patients with severe hypertriglyceridemia.
00:01:58.159 --> 00:02:06.079
These are not FCS patients, these are just the severe hypertriglyceridemic patients that many of us see in our in our clinics.
00:02:06.319 --> 00:02:11.759
So, Christy, if you can uh sort of start us off with you know what are the objectives of these studies?
00:02:11.919 --> 00:02:15.680
What were the entry criteria and the baseline characteristics?
00:02:17.039 --> 00:02:27.919
Peter, uh you know that by definition, we classify severe hyperclostemia as uh greater than or equal to 500 milligrams per deciliter.
00:02:28.639 --> 00:02:33.360
Now, chylomicronemia is what we always think of, that's the worst situation.
00:02:33.439 --> 00:02:37.039
And you know, in the United States we've talked about that as a thousand milligrams.
00:02:37.280 --> 00:02:42.000
In Europe, they do 10 millimoles, which would be 880 uh milligrams.
00:02:42.319 --> 00:02:44.639
But that's when you have childomicrons.
00:02:45.520 --> 00:02:53.360
It's important to also understand is the people who go into these studies, they just don't have a single episode of over 500.
00:02:53.439 --> 00:02:59.039
That they they get into the trial because they have persistent, severe hyperstruxinemia.
00:02:59.120 --> 00:03:11.360
And you you and I know that a lot of times you if you just you know, secondary factors, lifestyle diet, put them on a fibrate omega-3, you will get most of the people down below 500.
00:03:11.520 --> 00:03:14.319
But there are other tough ones who you can't.
00:03:14.400 --> 00:03:17.840
Uh, and sometimes it's genetic factors, polygenic.
00:03:18.639 --> 00:03:25.520
For example, the baseline characteristics here, uh, you had about half of the people with diabetes.
00:03:26.080 --> 00:03:27.759
BMIs 3031.
00:03:27.840 --> 00:03:44.560
So that's a typical scenario we're we're seeing is you know, uh 25% anti cardiovascular disease, but uh the the metabolic syndrome patient who has insulin resistance or diabetes, and really tough to control the triglycerides in these people.
00:03:45.120 --> 00:03:52.879
Uh you had there was uh 7.6 millimoles was the median triglyceride, and that's you know, around 700.
00:03:52.960 --> 00:03:55.680
So that's a that's a high median level of triglycerides.
00:03:56.000 --> 00:04:01.280
One of the things that comes in the study, about 20% had a history of pancreatitis.
00:04:01.520 --> 00:04:03.919
So that's a very important factor.
00:04:04.000 --> 00:04:13.439
Uh is the most severe complication that we're worried about for people with you know these persistent elevations is they get pancreatitis with it.
00:04:13.759 --> 00:04:30.639
So it's a I think an important clinical group, uh severely labeled triglyceritis, mean age was about 50, lots of people with diabetes, a bunch of people with cardiac disease, and also a bunch of them who had had pancreatitis uh in the past.
00:04:31.040 --> 00:04:33.680
So they didn't have to have pancreatitis to get in.
00:04:34.319 --> 00:04:34.879
Right.
00:04:36.319 --> 00:04:42.000
No, about 20% of them had had a history of pancreatitis, so it did not require a history of pancreatitis.
00:04:42.399 --> 00:04:49.839
So the objective of the study was just to look at what cosascerin did on triglycerides alone or anything else?
00:04:50.319 --> 00:04:54.319
Well, that's the primary endpoint was looking at the reductions in triglycerides.
00:04:54.720 --> 00:04:57.279
Of course, they want to see that they lower ApocryI.
00:04:57.360 --> 00:05:08.879
That's uh the way the drug works is you know, blocks the the uh step of going from messenger RNA to protein by degrading the the the messenger RNA to ApoC3.
00:05:09.199 --> 00:05:13.040
Apoc three went down a lot of triglycerides went down 80 percent.
00:05:13.199 --> 00:05:19.600
Now the placebo group went down some too, and that's what we see sometimes when people with high triglycerides get in a trial and get seen a lot.
00:05:19.680 --> 00:05:23.199
You tend to see the triglycerides going down uh with it.
00:05:23.360 --> 00:05:28.879
Uh so and and and if you had colomicronemia, they went down about 85%.
00:05:29.279 --> 00:05:34.800
So if you looked at getting below 500, it's like 91% of the people got below 500.
00:05:34.959 --> 00:05:36.480
A lot of them got below 150.
00:05:36.560 --> 00:05:46.160
So very big differences compared to the placebo group in regards to triglycerides reduction, and in a group that's been tough to treat.
00:05:46.319 --> 00:05:47.600
So that's the first part.
00:05:47.759 --> 00:06:07.600
But I thought I think the part that was the the most impressive overall is that there was a reduction highly significant in pancreatitis, uh 0.22, so is that 78% reduction uh in pancreatitis, the NNT was 24, 4.1 percent absolute risk reduction.
00:06:08.319 --> 00:06:24.480
So uh that's encouraging what was really pretty spectacular was if you'd had a prior episode of pancreatitis, then the the it was the you know, like a ninety one percent reduction, the NNT was three.
00:06:25.519 --> 00:06:31.439
I mean, so you know, that that's so that's I think something that's you know really exciting.
00:06:31.519 --> 00:06:47.279
And and the people who had colomicronemia who came in, uh, you know, they didn't have any episodes of pancreatitis, but so but it it was interesting, you know, some of the people came in over 500 with a past history of pancreatitis, there was benefit there.
00:06:47.439 --> 00:06:58.800
Uh so it's not just and you know, as you know, you and I have known, Peter, that you have somebody and you see when they're at 650 or 700, that's after a long fast.
00:06:59.519 --> 00:07:05.519
And you know, we we've seen, you know, we did the post-perennial studies back in the day with the Patch Brothers and Henry Power and all them.
00:07:05.920 --> 00:07:09.920
You know, that's the best they're gonna be all day.
00:07:10.800 --> 00:07:24.160
And they go to the have a big weekend on the town and have some Mexican food in Cervesas and margaritas, that 650 or 700, if they have a bad weekend, it could be three or four thousand, you know.
00:07:24.240 --> 00:07:27.199
I mean, we we you know, and then they end up in the hospital with pancreatitis.
00:07:27.279 --> 00:07:35.439
So you know, the the person to me, one of the big take-homes is just as you said, uh, you know, with the with this is not FCS.
00:07:36.160 --> 00:07:43.279
This is severe h elevations of triglycerides, including that group that's 500 to 880 uh with it.
00:07:43.360 --> 00:07:52.560
But uh, you know, one of the things is you know, I just this issue of uh pancreatitis, uh you know, and with we get it with heart attacks.
00:07:52.639 --> 00:07:55.279
If someone's had a heart attack, we know you got a lower LDL.
00:07:55.920 --> 00:08:09.199
Uh this the the data's you know, the in the pre previous trial uh with uh uh you know the the ASO also looked very good uh uh with in terms of reducing you know uh pancreatitis.
00:08:09.279 --> 00:08:18.399
So we've got two therapies, these RNA targeting therapies showing the tremendous benefit in these uh individuals.
00:08:18.879 --> 00:08:32.080
Yeah, I mean I I know that the plazasterone and which is the s irna and olizarsin, which is the antisense, the apple C3, they're already approved for the rare condition of familial color micronemia, right?
00:08:32.559 --> 00:08:33.279
Correct.
00:08:33.600 --> 00:08:34.080
Correct.
00:08:34.159 --> 00:08:42.799
And so and then uh and then olezarcin was recently approved for severe hypertrozoidemia.
00:08:42.960 --> 00:08:48.720
So this data will be submitted to the FDA for Plozasserin uh for the same indication.
00:08:48.879 --> 00:08:53.600
But you know, the it it's a it's really nice to see, you mean you this has been a struggle.
00:08:53.759 --> 00:09:02.559
We waited a long time to be able to treat FCS, but as you pointed out, we mentioned it, most of the patients don't have pure FCS.
00:09:02.960 --> 00:09:16.960
And I don't even like the name, you know, FCS versus MCS multifactorial, because the person who doesn't who can the person who comes in there, triglycerides keep running 1500, 2000.
00:09:17.200 --> 00:09:20.399
Well, most of us could never get there no matter what we ate.
00:09:21.200 --> 00:09:27.039
They usually have something genetic, you know, and familial colomicrone syndrome.
00:09:27.120 --> 00:09:38.159
And if you're if you have a pathogenic variant LPL and you get a bad polygenic risk score and some genes for diabetes, well, that's familial, as far as I'm concerned.
00:09:38.399 --> 00:09:44.159
I mean, that person is, you know, I don't know why they shouldn't get the medication because they're not the rare biolic.
00:09:44.399 --> 00:09:52.799
And so this is really good news, I think, for these tough-to-treat patients that we have uh uh, you know, the data that the therapy works.
00:09:53.120 --> 00:10:00.399
Yeah, I mean, I think this is this is wonderful because they, you know, they they struggle to take fibrates, they struggle to take high dose omega-3 fatty acids.
00:10:00.480 --> 00:10:07.600
And even with those, sometimes we can't keep people fluctuating above 500 and more with food they eat and a variety of things.
00:10:07.759 --> 00:10:21.519
So having these drugs available is going to be fantastic in in reducing their risk of uh particularly pancreatitis, which I think can be you know think it, a fatal disease when they um when they have it.
00:10:21.679 --> 00:10:28.399
So well, I guess the the the question is this is a the study with shaft of three and four was a single dose, right?
00:10:28.480 --> 00:10:30.799
It was 25 milligrams given every three months.
00:10:31.440 --> 00:10:33.120
25 milligrams every three months.
00:10:33.200 --> 00:10:33.840
That's correct.
00:10:34.240 --> 00:10:36.480
And it was two to one randomization.
00:10:36.720 --> 00:10:40.879
So, you know, the study's uh one 200 to 100 and about 300 to 150.
00:10:40.960 --> 00:10:47.120
So good two good size studies, uh very similar results, reassuring safety looked good.
00:10:47.200 --> 00:10:53.519
The glucose, you know, there can be some increase, but if you look during the duration of the studies, glucose was maintained.
00:10:53.600 --> 00:11:02.159
You can usually modify something in the therapies to get that that well controlled, and that weren't really seeing any other uh problems besides that.
00:11:02.240 --> 00:11:05.759
There was a hepatic fat small substudy, didn't see anything there.
00:11:05.919 --> 00:11:09.519
So uh overall uh looked look to be uh safe.
00:11:09.840 --> 00:11:14.720
You get an occasional injection site reactions, but those are usually mild and self-limiting.
00:11:14.960 --> 00:11:20.639
Yeah, how many how many of the patients actually got down to a level of normal triangles or less than 150 in these trials?
00:11:20.799 --> 00:11:21.519
Were there any?
00:11:21.919 --> 00:11:24.159
So it oh yeah, there were a lot.
00:11:24.320 --> 00:11:30.639
I mean, you know the uh uh you you had 90 percent getting under uh uh 500, 91%.
00:11:31.279 --> 00:11:35.360
And I forgot the exact number, but I think it's about uh 25, 30 percent.
00:11:35.440 --> 00:11:36.960
I mean, the odds ratio was 12.
00:11:37.279 --> 00:11:44.080
If you got the you were 12 times more likely if you got treated to get there than if you got a placebo, but you know, getting under 150, that's a that's a challenge.
00:11:44.159 --> 00:11:45.600
But it was quite a few people got there.
00:11:45.679 --> 00:11:48.320
It's so you know, really robust reductions.
00:11:48.399 --> 00:11:53.600
Uh, you know, and people in the trials and you see them a little more often, they they tend to do quite well.
00:11:53.679 --> 00:12:01.039
But I think one of the nice things is something that lasts every three months, it it's the therapy still has benefits up to six months.
00:12:01.120 --> 00:12:04.879
So if someone's a little late, you know, it's not gonna all wear off, which is nice.
00:12:04.960 --> 00:12:11.519
As you know, one of the reasons these people are hard to treat is some of them they they have a hard time being compliant with everything.
00:12:11.600 --> 00:12:15.200
It's because it's you they got to be strict on the diet, the exercise, taking the medications.
00:12:15.279 --> 00:12:20.720
So having something that has some durability is it it's nice to get a little safety margin there.
00:12:21.039 --> 00:12:24.480
Yeah, you know, one of the one of the final things I want to uh talk about.
00:12:24.639 --> 00:12:34.799
We've struggled over three decades trying to come up with a a therapy that we could prove that lowering triglycerides and triglyceride-rich lipoproteins can reduce cardiovascular disease.
00:12:35.039 --> 00:12:38.240
Do you think that there will ever be a cardiovascular outcomes problem?
00:12:39.759 --> 00:12:45.360
Or oasarcin to to try to prove that we can reduce cardiovascular events?
00:12:45.759 --> 00:12:56.080
You know, I I thought we had one that was gonna start in uh that there were a couple of them, uh, but uh uh you right now no one's pulled the trigger on these things, Peter.
00:12:56.159 --> 00:12:57.919
So we'll have to we'll have to see.
00:12:58.080 --> 00:12:59.360
I certainly hope so.
00:12:59.440 --> 00:13:02.960
Uh it's a very important studies.
00:13:03.039 --> 00:13:11.200
Uh that there was going to be one comparing uh Apo C3 SRNA to the NHB TL3 along with Oplus C, but that would have been an incredible trial.
00:13:11.279 --> 00:13:12.879
But it would have been very big and costly.
00:13:12.960 --> 00:13:20.799
So I understand sometimes the the companies, you know, have a they it's a lot, there's a lot of risk in there.
00:13:21.279 --> 00:13:22.639
Yeah, there is one thing we need to.
00:13:23.679 --> 00:13:25.200
We do need the study.
00:13:25.519 --> 00:13:32.240
Well, I know we we already know that uh genetically, if you're if you're loss of function, APO C3, you have a low risk of cardiovascular disease.
00:13:32.320 --> 00:13:44.000
So yeah, here we've got drugs that uh can can knock that out, so it should give you over time a reduction in cardiovascular disease in some of these high-risk patients, like you had in the SHAs to three and shaft to four study.
00:13:44.159 --> 00:13:45.279
Yep, yeah.
00:13:45.919 --> 00:13:50.320
So, well, this is any any other final comments about do you think this is enough?
00:13:50.799 --> 00:13:52.399
No, it's it's too much.
00:13:52.559 --> 00:13:53.679
I think it's exciting.
00:13:53.759 --> 00:13:59.759
Uh yeah, you know, I it looks to me that the the the study hit the objectives.
00:13:59.840 --> 00:14:06.639
I mean, that's what the decision for the FDA, but everything looks quite good from uh the data that's been presented.
00:14:06.799 --> 00:14:11.600
Uh the manuscript will be coming out soon uh with it.
00:14:11.759 --> 00:14:14.879
And so uh, you know, I think it all looks really promising.
00:14:15.120 --> 00:14:17.519
It looks it'd be similar to what we have.
00:14:17.600 --> 00:14:26.240
We have there'll be two agents, which is always also nice because get into a little bit of a price war there, uh, and also tends to make it easier for our patients to get something.
00:14:26.399 --> 00:14:29.200
But uh it looked very impressive.
00:14:29.279 --> 00:14:31.679
And the one thing was this NT of three.
00:14:32.000 --> 00:14:40.960
I think one take-home is if someone has had pancreatitis, they're at a high risk for getting it again, and they don't have to be over a thousand.
00:14:41.039 --> 00:14:47.919
If if they're running consistently over 500, that's a high-risk individual who certainly will benefit from treatment.
00:14:48.240 --> 00:14:48.799
Absolutely.
00:14:48.879 --> 00:14:51.120
So you said the the data will be published soon.
00:14:51.200 --> 00:14:54.559
Do you know where the Shasta 3 and 4 will be published?
00:14:55.840 --> 00:15:00.240
I do know where, but I'm not sure if if it's if it's supposed to be public information yet.
00:15:00.320 --> 00:15:02.639
So, anyways, it should it should be soon.
00:15:03.200 --> 00:15:05.120
Okay, okay, that sounds fantastic.
00:15:06.000 --> 00:15:07.120
It's a very good journal.
00:15:07.360 --> 00:15:08.639
Yeah, okay.
00:15:08.960 --> 00:15:20.480
Well, listen, Christy, I know uh you're still over there in Europe, and I appreciate you taking the time to to uh do this uh late breaking uh uh lipid uh insight podcast with me.
00:15:20.559 --> 00:15:24.639
I really appreciate it, and thank you so much for for taking that time.
00:15:24.720 --> 00:15:30.639
And I want to thank everybody else for uh taking the time to listen to this uh uh breaking data.
00:15:30.799 --> 00:15:31.200
Thank you.
00:15:31.519 --> 00:15:32.639
Always a pleasure, Peter.
00:15:32.720 --> 00:15:33.519
Thanks.
