0:00
We're a development stage organisation and we have a pipeline of products for which we're targeting disease causing proteins that are both diagnostics and prognostics of an organ fibroid, inflammation.
0:17
Just to sort of level set here, this is simply a survival curve comparing the survival probability of a patient diagnosed with heart failure and preserved ejection fraction, which represents about 50% of the heart failure cases.
0:33
Comparing that to stage 4 lung cancer, that's so at five years it's about the same meaning that it's about less than 50% survival probability if you have a diagnosis of HFpEF of heart failure.
0:48
So quite a bleak diagnosis and certainly requires a lot more innovation here in novel therapeutics, but also in precision medicine based approaches.
1:01
So talking about data here and just to kind of frame the situation.
1:06
So as many of you I'm sure very familiar Ozempic, Mounjaro, super popular medicines, if you read the clinical literature, randomised clinical trials, we'll put the weight reduction for both around 15 to 25% at 12 months.
1:26
However, if you look at if you look at the 12 month real world evidence, so you're on the right hand side, 12 month, this is semaglutide, you got about 7%, right, it's not 15%.
1:39
And tirzepatide, one year it's about 15%, not 25%.
1:44
All right.
1:45
So that's one thing we were to take away.
1:47
The other one is that if you look at cardiovascular outcome studies, what is very clear is the more weight reduction is accompanied by more cardiovascular mortality reduction and the gold standard bariatric surgery in terms of weight loss gets you there, but that is 30% weight reduction.
2:06
So certainly these are very important medicines, Ozempic, Mounjaro, et cetera.
2:11
But we're far from the target that is needed to truly address the heart failure unmet medical need.
2:22
So what we have developed using a big data workflow looking at unhealthy adipocytes and fibroblast is to identify a short list of actionable disease causing proteins for which we have developed molecules that can neutralise these disease causing proteins.
2:47
We have two therapeutic antibodies, they're both first in class.
2:51
One of them is PRV-101, which is a neutralising antibody targeting endotrophin and we'll talk about endotrophin.
2:59
And then 501 is a second programme, completely independent, also first in class, but also identified as part of the same workflows, just focused on different unmet medical need.
3:15
Now this is a schematic of how we think about precision medicine and it's starting with where we are today on the left hand side where you might have a syndrome and cardiologist key opinion leaders that we're working with often use that term syndrome to define heart failure with preserved ejection fraction.
3:36
You'll dig a little bit deeper.
3:38
We realised that there is some initial pheno grouping of the syndrome, so it's a little bit more precisely documented in the research literature.
3:48
But the reality is we're far from precision, which is what that little green set of circles is intended to depict, which is a much deeper pheno grouping, a much better molecular endotyping, which then allows us to identify the right patients that are going to be treated with our medicine at the right time, which is the blue dot, right?
4:09
So that's how we think about precision medicine, a very simple conceptual framework.
4:15
This is a team.
4:17
It is, I would just want to say just without getting into a lot of the details here, it is a very good collaboration between academia and biotech.
4:24
And I think that's part of the, you know, secret sauce here at PriveBio.
4:29
We've obviously got a team of drug developers and you know, deep dives into data and preclinical and of course clinical developments.
4:41
We have been fortunate that many of the cardiologists that we've talked to are very interested by our approach because they realise the unmet medical need, number one.
4:52
And 2nd is the lack of therapeutic innovation over the past decade plus.
4:57
Yes, standard of care is available and there was a slide that I didn't want to get too much into.
5:03
You can see some improvements, but I will just mention that a patient with HFpEF on standard of care today when diagnosed with an advanced diagnosis of HFpEF has about a 50% chance of worsening of its disease or even worse death.
5:21
So the standard of care is definitely upon us.
5:24
Obviously there are therapeutics, but there's a huge unmet need that is still upon us. At this fundamental level.
5:32
PRV-101 this neutralising antibody against endotrophin is targeting adipocytes and fibroblast in a way to take out a disease causing protein that gets secreted from these cells and then causes multi system malfunction.
5:50
But at a cellular level, our targets are fat cells and fibroblast.
5:56
Now when you take sort of a half step back and you look at the manifestations around HFpEF, yes, it often occurs in people that are obese.
6:05
So in the western definition of obesity, you know 30 plus BMI.
6:11
But it also very often can be traced back to adipocytes, fat cells, both visceral but also locally in the heart, like in the epicardial adipose tissue, and also fibroblasts, yes, perhaps all over the body, but also specifically located in the heart.
6:30
So what is endotrophin?
6:31
So endotrophin emanates from the upregulation of collagen subtypes, in particular 683, where when adipocytes and fibroblasts are dysfunctional, they increase their extracellular matrix.
6:47
It's part of a, let's call it, you know, [would] healing like type of cascade of injury and healing.
6:54
On an aside, I'm sure many of you recall from your class work, you know the classic cascade inflammation, fibrosis, inflammation, fibrosis.
7:04
Actually what we think we're on to is fibrosis, inflammation, fibrosis, inflammation.
7:10
So conceptually behind the biotech drug developments paradigm, there might be actually something much deeper here that is happening in terms of thinking about disease progression in a different way where fibrosis might appear first, then inflammation and then back to fibrosis, etcetera.
7:27
But the point here of this slide is that at the very end of collagen 6, alpha 3, C terminus you have 77 amino acid that get readily cleaved by a multitude of MMPs to release this polypeptide of 77 amino acid 8 kilodalton into the bloodstream or potentially acting locally.
7:47
We have a diagnostic developed to measure endotrophin specifically in the blood.
7:55
So readily deployable ELISA based assay and the therapeutic with the intent of course neutralising and endotrophin.
8:05
Just very briefly in terms of prognostics, this is not from US 2022 New England Journal BMS Bristol-Myers Squibb.
8:12
Looking at what they identified at that time was their number one prognostic indicator in HFpEF heart failure with preserved ejection fraction and they were basically tracing survival probability in these Kaplan Myer curves here on the left relative to different levels that ET endotrophin, you can see here in the yellow 11 nanogram per mil or less, that's about normal. Normal is around 10-11 And then compare that to the red right, 16 nanograms per mil or higher, you get about a 50% drop.
8:42
So that's just one example of having a lot of endotrophin is bad news.
8:50
To add on to that, when they also went on to demonstrate was that endotrophin was actually a more robust prognosticator compared to a risk score called MAGGIC or a very classic biomarker ProBNT that outperformed them both in terms of death or rehospitalization.
9:07
So based in part on that, FDA came out with a letter of support encouraging sponsors to now measure endotrophin in the heart failure trials.
9:16
Again, separate from us, there was a paper in Nature that clearly pointed to the causal role of endotrophin in coronary artery disease.
9:25
So they used in this case UK Biobank and deCODE to actually hunt for novel actionable proteins that are to be incriminated in the further development of coronary artery disease.
9:37
They looked at over 1000 proteins out of that ranking.
9:40
They are not endotrophin ECM people.
9:42
They are cardiologist, epidemiologist, looking for things that make sense.
9:47
Endotrophin though, was their number one culprit, followed by it was an interesting internal control PCSK 9 for which we know there are effective drugs.
9:57
So that really also reinforced the implication of this particular protein in human data.
10:03
And then we've added you know additional data ourselves.
10:06
Some of it has been published, some of it is not.
10:09
This is published data where we looked at HFpEF versus HFrEF over standard deviation away from the mean on the Y axis incidents.
10:19
And you can see here this nice correlation and patients with HFpEF, this is about 4500 altogether samples, but no such correlation with HFrEF.
10:28
So again, we're not at a very molecular level just yet, but we've ruled out HFrEF and we're really focusing here on HFpEF.
10:38
OK, so this is just a summary of all the data that's out there that basically points to the prognosticator impact of measuring endotrophin.
10:48
Long story is that if you have a lot of endotrophin to begin with, it's bad news.
10:52
There are data that we're going to be ready to publish soon where we've done some Cox regression analysis.
10:57
The patients with the worst outlook with HFpEF are the ones that have the most endotrophin.
11:03
And then across a number of different cardiometabolic diseases.
11:07
Clearly, you can see here that the hazard ratios, the odds ratios are really unfavourable when you have a lot of endotrophin. Indicated here in this middle box right here, we've done Mendelian randomisation in heart failure and diabetic kidney disease and we do pass the threshold of, you know, nominal P value suggesting that there is a signal there also beyond coronary artery disease.
11:34
What's even more interesting here is there's a dose dependency actually that's emerged, meaning that for every one nanogram per mill increase of endotrophin that's measured in the blood, you got about a 14% increase in all-cause mortality, right?
11:47
So from a PK/PD perspective, it's starting to feel a lot like, OK, we understand what we have to go after, we understand how much we need to reduce it by and we understand what the outcomes of that reduction is going to be.
12:02
Just on an aside, when you have Mendelian randomization or biomarker, your odds of getting a drug approved from when you start first in human to approval goes at least three times higher than if you don't have that.
12:14
So it's pretty good.
12:16
It's not perfect, but it does put us on a direct path to who are the patients and what is the right clinical trial and then the timeline for detecting these effects.
12:30
These are some of the features of the therapeutic antibody that's been developed.
12:34
And it's a tight binder, 1.9 nanomolar Kd.
12:38
It's a full neutralizer.
12:42
You know that from cell based assay reverses the E max back to baseline when you've added endotrophin.
12:47
And then we've dosed the antibody across dozens and dozens of different animal models and we've shown excellent efficacy, which I'm going to be just showing here in a second.
13:03
So just a little bit of data.
13:05
We do actually have a crystal structure.
13:06
So we truly understand the contact points here between the ligand endotrophin that we're targeting and these therapeutic antibodies.
13:13
We've covered up the structure of endotrophin for IP reasons and then you know, we've produced it with a manufacturing partner.
13:22
It behaves super well.
13:23
So far so good.
13:26
It looks like we have a drug in our hand.
13:28
We understand the patient population, we understand how much we need to reduce endotrophin by and we just have to get to the clinic and do the experiment.
13:36
I'm going to show you a little bit of preclinical data, right.
13:40
So that was a lot of human based patient derived data.
13:42
So at the cellular level you add endotrophin onto any one of these cells, you get an effect.
13:50
So this is a little bit of the data here that sharing with you.
13:55
So upper band here are quantitative mRNA measurements of a number of ECM related genes, collagen subtypes, TGF beta, TGF beta R2.
14:09
When you add endotrophin and compare even to TGF beta, you have clearly an increase in fibrotic genes.
14:19
When you look at the bottom left here, these are human hepatic stellate cells where we've treated them with endotrophin.
14:26
We then measure collagen I A1 increase in mRNA.
14:30
We can reverse that with the neutralising antibody and as you dilute the amount of antibody, you can see here the reversal back to the E Max with full dose of endotrophin, we activate the SMAT pathway.
14:41
We also activate JNK and ARC, we activate macrophages.
14:44
We can reverse that activation also with the antibody.
14:48
These are cool experiments.
14:49
So this is an experiment where mice, garden variety mice were infected with an AAV that specifically was designed with a troponin tube, so a cardiac myocyte specific promoter upstream of endotrophin.
15:05
So it only expresses endotrophin and cardiac myocytes and you actually can get heart failure like disease in these mice, just with the specific expression of endotrophin in cardiac myocytes.
15:17
Let me start with the first here on the right hand side.
15:21
Exercise intolerance, right heart failure, can't walk up the stairs as much.
15:25
Certainly heart running becomes harder.
15:27
That's what happens in these mice.
15:29
They run less.
15:30
The dark yellow here is the endotrophin AAV infected mice.
15:35
Then if you look just next to the red box here, fibrosis.
15:39
So this is cardio fibrosis.
15:40
There's an increase very clear here of cardio fibrosis that's associated with this up regulation of endotrophin expression and myocytes.
15:48
And then if you look on the EF panels, you can see here features of HFpEF symptoms that are seen in patients.
15:58
The diastolic function here, E over E prime is getting worse.
16:03
So you can see here from the grey to the yellow.
16:06
And then the atrial area also is increasing and you're preserving ejection fraction, right?
16:11
The HFpEF, LDF, you can see here left ventricular ejection fraction stays the same, right?
16:17
So it's remarkable actually we have seemingly a very clear disease driver at least in mice and with all the human data correlating sort of to the targeting of this agent.
16:32
Just very briefly here, so different set of experiments here.
16:34
So instead of taking garden variety mice, now you take mice, you give him high fat diets and then you make him hypertensive for 10 weeks, very consistent with the fact that 80% of patients with HFpEF in the US are obese.
16:52
And then you administer an antibody that neutralises endotrophin.
16:55
And what you're seeing here is a reversal of their exercise intolerance.
17:00
So let me just quickly walk you through the left hand side here at the bar graphs.
17:04
So green is what you see when you give mice regular chow.
17:08
Pink is what happens when you give him this HFpEF diet, right?
17:11
High fat plus L-NAME to make him hypertensive.
17:15
And you can IgG 1 isotype control nETP neutralising endotrophin antibody.
17:19
You can see here the two pinks, right?
17:22
The big difference, right?
17:23
So HFpEF diet, the mice run half the distance you give them that neutralising endotrophin antibody, you can reverse that exercise intolerance.
17:32
And then we've made the knockouts.
17:34
And the knockouts, to make a very long story short, are also protected from developing heart failure phenotypes.
17:40
We're just measuring diastolic function here.
17:42
Should mention at baseline, there is no phenotype with these knockouts.
17:48
And let me just skip over this, just going to maybe just show this one last slide of data here and then we can wrap up if you have any questions.
17:59
We've also done an experiment where we've expressed endotrophin specifically in adipocytes, fat cells using an adiponectin promoter that's driving endotrophin.
18:11
So these are genetically modified, they're transgenic and you can see here in the red in the left hand side, these are the endotrophin expressing mice.
18:22
And you can see that a number of markers of fibrosis, a number of markers for inflammation F4/80 SAE3 are all increased by endotrophin.
18:34
And then if you look at the oral glucose tolerance test here, the mice are definitely becoming insulin resistant.
18:40
So this gives you sort of another perspective on the fact that you have a driver locally of pathology of heart failure.
18:50
You now have a systemic disruptor of metabolism.
18:53
So things are starting to really line up in this sort of multi system organ manifestation that's driving a lot of the metabolic syndrome that is associated with heart failure.
19:05
So that's all I wanted to just cover with you today in terms of preclinical work.
19:11
And just to briefly wrap up here, so this is our clinical development design.
19:17
You know, it's a pretty standard Phase 1A and then a Phase 1B here that is designed at the end here to provide us with answers in heart failure.
19:27
But also, and we didn't talk about kidney disease a lot, but we're also targeting a kidney disease.
19:33
So thank you so much.
19:35
If we have time, if you have any questions I'd be happy to answer them.