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You are listening to First in Human, where we interview industry leaders and investors to learn about their journey to in-human clinical trials Presented by Vile, a tech-enabled CRO Hosted by Simon Burns, ceo and co-founder.

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Featuring special guest host Amy DelMedico, vp of Ophthalmology.

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For this episode, we are joined by Josh Mandelbrum, ceo of Camp4 Therapeutics, as he delves into the innovative world of RNA amplifying therapeutics and their potential to revolutionize treatment for a range of genetic diseases.

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Hi everyone. I'm Amy DelMedico and I'm here today with Josh Mandel-Brem from Camp 4 Therapeutics.

0:51

Josh, welcome. Would you like to give a little introduction on yourself?

0:55

Great, yeah, first of all, thank you very much for having me, amy.

0:58

It's a pleasure to join you today. So I'm Josh Mandel-Brem.

1:01

I'm the CEO of Camp 4. Prior to Camp 4, I was at Biogen and Genzyme in business development and strategy roles, and really looking forward to talking with you today about Camp 4.

1:12

Great, thank you. So my first question is could you give us some background on Camp 4 Therapeutics and maybe touch on the meaning of the unusual name?

1:20

Yeah, absolutely, and I love when people ask that question, so maybe I'll start with it.

1:24

So Camp 4 is the last camp for the top of Everest.

1:27

It's also a sacred ground in Yosemite National Park where all the world's best rock climbers come to push the boundaries of what's possible boundaries of what's possible in order to make better treatments for patients.

1:46

That was something where we felt very strongly that it wasn't grounded in a scientific name but more of an aspirational name, because we have big intentions for what we can do with our platform, and so, on that note, you know what is CAMP4?

1:56

Camp4 in its simplest form is using what's called antisense oligonucleotides, a form of chemistry, to very specifically increase the expression of genes.

2:06

And how do we do this is an area of biology called regulatory RNAs.

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These are RNAs that come out of our non-coding genome, so they come out of enhancers and promoters.

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They have two really important features.

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One is they act on nearby protein-coding genes to control the expression of those genes, and they act within what we say a physiological range, that is, they allow for increases or decreases to genes in a range that the cell can handle, so a safe range, if you will, so avoiding toxicity.

2:37

So I like to think of regulatory RNAs as built-in specificity, and what we have discovered at Camp 4 is that when we find a regulatory RNA that is influencing the expression of a gene that is tied to disease, we can drug that regulatory RNA with an antisense oligonucleotide in a very specific way and we can increase the expression of the remaining healthy gene, which then allows us to go off a range of diseases that have a genetic basis where you're missing a little bit of protein, and the difference between being sick or healthy can be putting that little bit of missing protein back into the system.

3:10

Interesting. Thank you for the background. It sounds like it could be applied to a broad range of different indications.

3:16

Yeah, the biology itself extends to any different tissue in the body, and I've referred to this before, but there's an entire category of diseases that are either haploid deficient meaning one of your genes no longer works but one is still remaining to be healthy so you're missing 50% of protein to be healthy or partial onset function you have a mutated enzyme that kind of works, but not enough, and so essentially there's hundreds of these diseases where there are no approved treatments, and what we've chosen to do is apply our platform at first into metabolic diseases, that is, the liver-based diseases or certain parts of the brain, and the reason for that is we know we can deliver this type of chemistry antisense oligonucleotides safely and effectively to those two tissues, which have a lot of diseases that have a genetic basis and are still in need of treatments.

4:05

So you've touched on it a little bit, but can you walk us through in more detail how the RAP platform works and how it amplifies mRNA and increases healthy gene expression?

4:14

Yeah, absolutely so. Our bread and butter is really what we call mapping cells.

4:18

What this means is we take a human cell type.

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So, for example, in the liver, we'll take a hepatocyte, and we will apply a whole range of different next generation sequencing technologies and we'll generate billions of different wet lab biological data points.

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And to make sense of that information, we actually have a data science team that has built algorithms that can then take all that information and turn human gene expression into an encyclical exercise.

4:44

So what I mean by that is, once we map a cell, any gene that is being expressed so the liver has maybe 11,000 protein-coding genes, whatever gene you're interested in we can very rapidly show you how the DNA is controlling that gene, and from that information we can pick out the RNA, the regulatory RNA that is controlling a gene of interest.

5:03

So that is step one when we apply our RAP platform, which is the RNA, the regulatory RNA that is controlling a gene of interest. So that is step one when we apply our rat platform, which is the RNA actuating platform.

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Once we have a target gene in mind so a gene that is underlying disease, where we want to increase its expression, to put more protein back into the body.

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We can then screen the sequence of that gene, that regulatory RNA, using antisensibonucleotide.

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This is a very tried-and-true chemistry.

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It was pioneered by the likes of Ionis and Olanol, two very well-established, successful companies that have approved drugs on the market.

5:33

We're using the same type of chemistry that allows us to make a very programmable and rationally designed antisense oligonucleotide that we can then deliver as a therapeutic to the patient where we want to increase gene expression, to essentially ship the unhealthy state.

5:50

And I know with your development program you're focusing on urea cycle disorders, which can be quite complex and severe conditions.

5:57

I wonder why you decided to choose that particular therapeutic area.

6:01

Yeah, so, not surprisingly, there are lots of different diseases that we could theoretically apply our platform to again that have a genetic basis.

6:10

So what are the things we think about when we choose diseases to work on basis?

6:15

So what are the things we think about when we choose diseases to work on? We'd like to work on as many as possible, of course, but we are a smaller biotech and so we have to be judicious with the resources.

6:20

So one thing that we think about is okay, what is the genetic basis of the disease?

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Is there strong evidence that if we increase the expression of a target gene, even by a little bit, it'll have a dramatic effect in helping patients?

6:33

The second thing we think about is the path to the clinic at how quickly and efficiently can we actually prove out our thesis in the human setting?

6:42

And that's really important, because sometimes the science is beautiful but you can't find the patients.

6:48

Sometimes the science is beautiful but you have to do a very long study to prove it out, or you need to find thousands of patients, which you'd wish to do, but, again, as a smaller company, you have to be really thoughtful.

7:00

So we try and find diseases where there's an unmet need, there's a strong genetic basis, and we think we can at least do the first clinical study to show that our drug works.

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And then the last piece is, of course is there a commercial market there?

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And that's really a lineup of what's the unmet need, what do we think our drug can do in terms of its transformative impact and what does competition look like?

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And so, in the case of urea cycle disorders, which I think we'll talk more about, this is a disease that has many different subtypes, meaning there are six enzymes that work together to essentially break down ammonia.

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And for all of us that are walking around healthy, we have an intact, healthy urea cycle.

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If you're unlucky enough to have a mutated enzyme in this cycle, although you may retain some partial activity, it's not enough to prevent the buildup of ammonia, which leads to all kinds of neurological side effects.

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It can lead to death very young, and so the idea for Camp 4 would be if we could increase the rate at which the cycle can break down ammonia to urea, we could have a massive impact for these patients, and not just one subtype, but almost all the subtypes of urea cycle disorder patients.

8:05

So we have a strong belief, based on the genetics, that a small increase could lead to a big impact.

8:10

We know that we can do a pretty efficient healthy volunteer study even though they're not sick.

8:15

But we have an assay we could look at to measure the rate of ureogenesis and we know that that will allow us to essentially set parameters directly to patient studies.

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And we know that this is a disease. Although it's rare 5,000 to 10,000 patients in the US have it it's a really crummy disease and these patients are in badly need of a therapeutic.

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So we like that from a commercial perspective where we think our drug can become a backbone therapy for these patients that so badly need new medicines.

8:40

And are your clinical trials focusing on just one of the subtypes?

8:43

So you mentioned it could potentially work on all, or are you looking at multiple subtypes?

8:49

We're looking at multiple subtypes. That's the grand vision for the drug and the way that we think about that is.

8:53

In this case it is a partial loss of function.

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It's not a haplosufficient disease, meaning most of the patients, regardless of their mutation, they retain some activity.

9:02

So we know there's an opportunity to boost that activity and what we've done is we've chosen a rate-limiting enzyme, so the first enzyme in the urea cycle that's rarely mutated, that if you increase that enzyme, the first thing it does is it immediately allows more ammonia to be converted, and the second thing that it does is it actually boosts the expression or the mRNA protein of additional downstream enzymes.

9:25

So we get a double impact from working on that particular enzyme and, because of what I just said, that theoretically allows us to go after the great majority of patients, despite having different mutations, if you will.

9:37

One other comment it would seem obvious to go directly into patients with our drug.

9:41

However, we felt that actually going into healthy volunteers, so normal people who have a healthy attack urea cycle, would be the way to go, because one it would allow us to ensure the drug is safe.

9:51

These patients have very fragile livers.

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And then the second thing is it would allow us to actually be able to deploy a new type of assay, relatively new assay, called the urea genesis rate test.

10:03

That is a way of measuring the activity to convert ammonia to urea, which is a stable isotope you want to get out of your body.

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So essentially it would allow us, even though it takes a step before you get patients.

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In the long run, it allows us to have tools that we think could facilitate regulatory discussions, that can allow us to better measure the activity of our drugged patients and essentially move more quickly towards an approvable product in the future, because that's our ultimate goal to get there as quickly as possible for patients.

10:31

In the same way, Interesting, so you're almost starting to develop your own endpoint.

10:36

Yeah, so there is an approval endpoint by the regulatory agencies, that is, the reduction of ammonia, which would make sense because that's the culprit that ultimately leads to symptoms.

10:44

But the more tools that we have to show a benefit in patients and help patients, the better it is in terms of our own probability of success and making sure we're running the best studies, and so whether or not it becomes a provable endpoint tool we'll see, but at the very least it's another tool we could use to the benefit of ourselves as well as patients.

11:03

I wondered if you could explain to our audience the dark genome and how it's being used to develop treatments for diseases.

11:10

So disclaimer, I did not come up with the dark genome.

11:12

I think that is a phrase that others have used, that you know we're happy to be included in that.

11:18

I'd say it's a very broad term and said simply of our DNA, 2% give or take of our DNA it codes for genes that make proteins.

11:26

Okay. The other 98% of our genome does not make proteins.

11:30

It makes all different types of important functional outputs that control the expression of genes, and the more and more we dig deeper into this that is the dark genome, and the more we study it, the more that we find that it turns out it's a very, very important part of how our bodies control cell fate, cell differentiation, gene expression.

11:50

So for our particular purposes, we are studying the areas of the dark genome that are enhancers or promoters, specifically that actually make a type of RNA, regulatory RNAs.

12:01

It does not code for proteins and, as I had said earlier, these RNAs in turn turn out to have a very important function in controlling the expression of nearby protein coding gene, the 2%, if you will, of genes in our body.

12:14

Fun fact is that although we only have 20,000 to 25,000 protein-coding genes, the same gene can be expressed in different cells.

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How is that? The way that cells get specific gene expression is because of enhancers.

12:27

We have many more enhancers compared to the genes themselves, and the enhancers are where the RNAs come out of.

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So that turns out to be a very, very important part of the dark genome.

12:37

There are other companies that are studying it because if there are mutations in those regions, they can lead to disease.

12:42

We've read that as well, so I think there's all types of opportunities that can lead to new targets or new ways of interpreting disease by studying the dark genome, despite the fact that diseases are typically looked at as mutations of protein code.

12:57

Thank you. It sounds like a complex and quite novel approach and I imagine there were quite a lot of challenges in developing your therapeutic CMP CPS-001.

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How have you addressed those challenges and can you pick out any in particular that have been a problem for you?

13:12

Yeah, I mean I always thought problems create opportunities, so we always try and look at it in that way.

13:17

Look, first of all, I think part of what we're doing is novel in the sense or a big part of it that we're the first company that's really taking antisense algonucleotides and instead of downregulating or degrading proteins or enzymes that are mutated, you don't want in your body, we're doing the opposite.

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We're using that technology to actually act on healthy genes and increase gene expression.

13:38

That's a completely novel way of thinking about the technology and really opens the aperture for a technology that I think has been proven to be safe and effective, is in approved products and is in many products in the clinic, but again, only in one half side of the coin.

13:53

That is the downregulation aspect of it.

13:56

So now, all of a sudden, we're taking something that is, I think, proven to be a therapeutic and we're teaching it a whole new way that it can be used to treat disease.

14:02

And the way we thought about it was well, we can't get tenfold increases in gene expression.

14:08

There are diseases where you really have to put a lot back in the system.

14:11

That seems like a problem. On the other hand, as I mentioned earlier, there are hundreds of genetic diseases where, actually, you only want to increase the gene a small amount and overexpressing the gene could lead to toxicity, and this area of biology does not really want to allow for overexpression.

14:28

It's like a built-in safety feature. So in this case, we took that challenge, that we took it into an opportunity set, which is this is perfect for all these haploid-sufficient diseases.

14:37

We don't have to worry about overexpression. That's not a major area of concern.

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We're much more focused on designing a drug that is specific to the RNA that controls the gene and we're highly confident if we could make a version of that that is safe, that it should have a big impact in the clinic.

14:54

But that's what we'll be proving out, and I say that based on our preclinical data.

14:57

So that's an example, I think, of a challenge where we took what the biology was doing and, instead of trying to make it do something it didn't want to do, we just directed it into a set of diseases where it fits perfect from our perspective.

15:10

That's just one example.

15:12

Excellent, thank you. We've mentioned that there's a potential range of therapeutic applications.

15:17

I wondered if, sort of beyond the UCD space, are there any other genetic diseases that CAMP4 is exploring.

15:25

Yeah, absolutely, and I kind of alluded to this a few times.

15:28

So, in the metabolic space, our first program is for urea cycle disorders, and we are in the clinic administering that drug.

15:34

Our next program is for a very interesting target.

15:37

It's the LDL receptor. This is a very competitive area.

15:41

Actually, there are many approved drugs in this area, for example, statins, pcsk9 therapies there's also an RNAi that's been approved for it as well, and the idea here is that there are millions of people walking around, some with a genetic basis that have LDL levels that essentially put them at high risk for cardiac events.

15:58

Now, in a decent amount of those patients, statins have been a very effective treatment.

16:03

Pcsk9 is another effective way to do that.

16:07

Those are more recent therapeutics that are based on genetics, by the way.

16:10

Yet still there are many, many patients that their LDL levels are remaining way too high, or they're not responding, or they have side effects from those other drugs I mentioned, and so maybe they could take one but not the other.

16:23

So, essentially, there remains a pretty big opportunity, despite the fact they're approved drugs, that if you can come up with other ways to remove LDL, you could help millions of people, and so our approach is, in fact, to directly up-regulate the receptor that ingests bad LDL and removes it from the system.

16:41

So it's a very clever way to essentially go about solving the problem, and we think that could be a really important treatment regimen in the context of the other treatments that are out there as well.

16:50

And again, that's because there's still many people that need to lower those LDL levels.

16:54

So that's another example of a metabolic program, and both those programs are subcutaneous delivery.

17:00

They're not infusion, they're injection, which I think is really important, especially given the fact that many of these fish don't want to go through infusions.

17:07

It's very cumbersome for them. So that creates an opportunity.

17:10

Now, in the central nervous system, one area that we're very keen to work on is genetic epilepsies, and so there are many different types of genetic epilepsies, for example, gervais syndrome, syngap, scn2a, where these are haploid sufficient.

17:24

One gene is no longer functioning, one gene is still functioning.

17:27

So essentially, you're missing 50% of protein to be healthy, and we have pretty high confidence that if you can shift expression even by just 50% meaning you put people back up to the 75% level based on genetics, that this is going to have a pretty big impact for patients, and we would call it disease modifying.

17:44

Most of these diseases have no approved treatments.

17:47

Some do, but a lot don't and these patients are really suffering.

17:50

The caregivers are suffering, probably because nobody's really ever found a way to address these diseases, either because not all modalities get into the CNS or it's very hard to do this with formal ligation.

18:00

So our approach of identifying a regulatory RNA that can control these genes that are underlying the diseases, using antisense oligodendymocleotides delivered intrathecally, that is, through the lumbar puncture, just like the approved drugs Spinraza for spinal muscle atrophy and Doverson for ALS, is a really nice way to essentially get the drug to the target where these patients have no other treatments and essentially are suffering from all types of different comorbidities, including seizures.

18:29

So that's the next category of diseases we're building in the brain, behind those metabolic programs.

18:35

Josh, thanks for the in-depth answer. I really appreciate it.

18:37

I've got one last question for you, so, looking ahead, I wondered what excites you the most about MRE and therapeutics?

18:45

Yeah, I mean said simply, the entire purpose of our company is to make drugs for patients right, and the more we get into this, the more we learn about different diseases where we think our technology could be applicable.

18:56

Into this, the more we learn about different diseases where we think our technology could be applicable.

18:58

And so what really excites me is that if we're able to convince people that this is not only a fundamental area of biology that we can take advantage of to make many new drugs, but that Camp 4 has the ability to make those drugs.

19:09

We know we can't do it all on our own.

19:11

We will absolutely shepherd things forward using our capital and resources, but I hope that it brings to bear other partnerships with bigger and smaller companies so that we can take advantage of our RAP platform and essentially bring more drugs to patients that Camp World can do on its own.

19:26

So I think that's really our big vision here.

19:29

We want to create the next great platform by playing companies.

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We know we can't do it on our own, but we think if we continue to show promising data, that that will bring to bear other ways of creating opportunities to bring drugs to patients.

19:41

Amazing. Thank you, Josh, so much for your time and for the very interesting discussion.

19:45

Appreciate it.

19:47

Yeah, thank you, Amy. It was really a pleasure to speak with you today.

19:58

Thanks for listening.