RNA therapies offer great promise for addressing rare genetic diseases by disrupting the translation of pathogenic genes into disease-causing proteins or getting the body to produce a needed protein it lacks. But the challenge of delivering these therapies to tissue where they need to go to be effective has limited the diseases that have been treated with these therapies to date. DTx Pharma has developed platform technology to address the challenges of delivering RNA therapeutics and is building a pipeline of RNA therapies. We spoke Arthur Suckow, co-founder and CEO of DTx, about the delivery challenge of RNA therapies, how DTx’s platform technology addresses these, and how a $100 million financing from earlier this year will be used to fuel its growth.

 

Daniel Levine:

Arthur, thanks for joining us.

Arthur Suckow:

Thanks for having me, Danny.

Daniel Levine:

We’re going to talk about DTx pharma, it’s Falcon technology, and how this has the potential to improve the delivery of RNA therapies. Perhaps we can begin with siRNAs. These are different than antisense oligonucleotides and micro RNAs. What are sRNAs and how can they be used to combat genetic diseases?

Arthur Suckow:

In the simplest terms, siRNAs are a mechanism that you can utilize to repress the expression of disease causing genes. They differ from antisense in that they act in the cytoplasm versus the nucleus. Additionally, they’re double-stranded molecules. It’s also worth pointing out that there is no chemical modifications that can enable siRNA molecules to get into cells unlike antisense. So, they need an approach like ours to be effective.

Daniel Levine:

Does this mean that for certain diseases, this is a modality that you can work where other RNA therapies wouldn’t work?

Arthur Suckow:

At the highest level, there are some of the advantages of siRNAs versus say an ASO approach. One, they’re intrinsically more potent. So, at concentrations that are oftentimes a hundred or a thousand fold less you can get potent or efficacious repression of gene expression. Two, they also tend to be a bit safer because you can get rid of some of the chemical modifications that cause some stickiness to cell proteins that are associated with ASO’s. And then thirdly, they have quite a long duration of action relative to antisense technologies. That’s not to say that there aren’t situations where we might use ISO’s. In general, our preference is to use siRNAs for those reasons. Situations where you might use an antisense would be in a situation called exon skipping, where you sort of skip over a mutant and exon in a gene to create a shorter but functional copy of a protein. An example of that would be with dystrophin for Duchenne’s.

Daniel Levine:

My memory of sRNAs is that they’ve been challenging to use as therapeutics because they have a short half-life and there’s difficult getting them to the cells within the body where they’re needed to act. Why have these been difficult in the past to get to where you want them in the body?

Arthur Suckow:

For almost all RNA therapeutics, the answer is almost always delivery. The first problem is that cells don’t take them up at all, and there’s not really any sort of chemical modification you can do to the backbone of the molecule to enable it to get into cells. The other reason is when you dose these things, they tend to be rapidly cleared within a few minutes by either the liver or the kidney, mostly the kidney in an unconjugated form. So, you don’t get opportunities to get into cells. Folks, over the course of the last 20 years or so, have tried all sorts of delivery approaches, with the primary one being lipid nanoparticles, to enable delivery. In the end there was challenges because those tend to distribute primarily to the liver. They also tend to be associated with cytotoxicity and oftentimes inflammation. So, they were abandoned by almost all companies, sometime between 2012 and 2015, in favor of approaches like GalNAc, which is a sugar that you coupled to siRNAs that allows it to get into hepatocytes, but only hepatocytes. To some extent that overcame some of the cell uptake and safety challenges, but not necessarily delivery to organ systems where there’s diseases and this class of therapeutics might be beneficial. The other thing that I might add is that over time chemists across a whole host of different companies have come up with chemical modifications to the nucleotide backbone of the siRNA, the A’s, T’s, G’s, and C’s, that render them really stable to endonucleases in the cells that want to chop them up. Then of course, they engineered out some of the propensity to engage the immune system in a non-productive way.

Daniel Levine:

DTx has a platform technology called Falcon. What is Falcon and how does it address the challenges of delivering siRNAs?

Arthur Suckow:

So, Falcon stands for Fatty Acid Ligand Conjugated Oligo-Nucleotides. The Falcon name, comes from my, high school mascot, we were able to make that work. In any case, when I came to the RNA therapeutics scene, we had noticed that fatty acids were quite a bit underexplored relative to our knowledge of the way they with both their receptors and the way that they interact with albumin. On the cell uptake side, every cell in your body has a mechanism to take up fatty acids, some even have specialized mechanisms. So, you could imagine leveraging those receptors and those transporters analogous to the way Alnylam, Ionis, and Dicerna have used the GalNAc receptor to bring molecules into hepatocytes. The other really cool feature of fatty acids in other contexts is that they are a tried and true mechanism to promote biodistribution. There’s actually four multi-billion dollar peptide drugs in the diabetes space that leverage covalently attached fatty acids to promote half-life. So, the way those molecules work is the fatty acids interact with a protein in the blood called albumin. Albumin, kind of serves as an Uber, to prevent clearance by the kidney and to maintain exposure of those drugs, the insulins, the GLP1’s, to the targets, the pancreas, the muscle, adipose, et cetera. So, that problem that fatty acids overcome for peptides is sort of the same fundamental problem that RNA therapeutics face, right? Rapid clearance by the kidney in a few minutes time without the fatty acid. We said this was a really underexplored space. So, we set out to do a screen that ultimately led to the identification of fatty acid motifs that not only enable cellular uptake, but they also improve biodistribution to tissues, like the Schwann cells or muscle cells. Then additionally, they were comprised of naturally occurring fatty acids amongst the most prevalent in your body. They’re of the same ilk that were used on those approved drugs. Of course, in a different context. That’s where we saw opportunities to deploy fatty acids.

Daniel Levine:

How did you come to look at fatty acids in the first place as a potential way to solve the problem of siRNAs?

Arthur Suckow:

Its through my experience at former employers. So, while I worked at Johnson and Johnson, I worked extensively in a diabetes space and we worked quite a bit on small molecules targeting fatty acid receptors. There, I learned quite a bit about the way that fatty acids engage their receptors, the confirmations, et cetera, but sort of through small molecules. Then, I went off to AstraZeneca, I was one of the founding members of a biologics group there. What we worked on there were antibodies, antibody conjugates, but a big part of what we worked on were fatty acid conjugated peptides for half-life extension and ways to engage albumin to keep things around in the circulation long enough so that they could engage their receptors. After spending some time in Gaithersburg, Maryland, I realized I missed San Diego quite a bit. So, I ended up jumping ship and moving to a company called Regulus therapeutics and that’s where I came to know the RNA therapeutics delivery challenge. They were on a downhill trajectory so I jumped ship. Based on my experiences with other modalities, small molecules and peptides, it seemed like there was an opportunity to consider using fatty acids to overcome some of the challenges that came to light during my time at Regulus therapeutics.

Daniel Levine:

When there are delivery challenges with modalities, we tend to see people go after indications involving the liver or the eye. It’s not surprising to me to see you have your lead indication in the eye. You have an experimental therapy for pan retinitis pigmentosa. What is pan retinitis pigmentosa, and how does it manifest itself and progress?

Arthur Suckow:

So, retinitis pigmentosa is essentially death of photo receptor cells in the back of the retina. These cells are the first cell that perceives light and starts a signal that talks to your brain that allows you to see. This disease can lead to rapidly progressing blindness or it can also progress quite slowly. But ultimately, it leads to quite significant vision loss across a hundred thousand patients in the U.S.. It’s also worth pointing out that there’s a hundred genes that are mutated and more than 300 different mutations. So, where the pan comes in, is the approach is meant to be, at least in part, agnostic to the underlying genetics driving the disease. If you have a mutation in rhodopsin or you have a mutation in another gene called phosphodiesterase 6B, this therapeutic, at least in the proof of concept animal models, will be predicted to work. So that’s what we mean by the ‘pan’.

Daniel Levine:

Well, you’re still in preclinical work on this, how would this be delivered?

Arthur Suckow:

It’s an intravitreal injection. We plan to dose it anywhere between once every three months to as infrequent as once a year. Our preclinical data certainly supports a very long duration of action following a single injection.

Daniel Levine:

What’s the timeline for beginning human clinical studies?

Arthur Suckow:

We plan to enter clinical studies next year, in the second half of 22. We released recently generated some exciting data in non-human primates that supports not only the approach, but the mechanism.

Daniel Levine:

What’s known about its activity from those preclinical studies?

Arthur Suckow:

We get upwards of 90% repression of the target gene, and that’s across the different species. Then of course in the animal models of retinitis pigmentosa, we can prevent the pathogenesis of the disease. Some of the endpoints that we look at include, ERG, which are just a fancy way to flashlight at the animal’s eyes and measure how well the photo receptors are firing. We do histological endpoints to ensure that the photo receptors are actually protected. Some of the KOL’s we work with have said, it’s some of the most striking data they’ve seen in terms of histology. Those are some of the things that we’ve been looking at pre-clinically to justify advancing the compound into patients next year.

Daniel Levine:

We recently featured Susan Ruediger from the CMT research foundation on the rare cast, which is focused on catalyzing drug development to treat Charcot-Marie-Tooth disease. This is a rare, degenerative nerve disease, that’s been difficult to treat, in part, because it requires targeting the peripheral nervous system. What makes your platform a compelling approach for a condition like this now that you’re working with the CMT?

Arthur Suckow:

It’s exciting that you talk to Susan. We love Susan at DTx. She and DTx have kind of grown up together. We’re really attracted to CMT 1A for a number of reasons. One of those is that it’s sort of a killer app for an siRNA therapeutic. The reason being is that the peripheral neuropathy you described is driven by a duplication in a gene, that gene is called PMP 22. So, the patients end up having three copies of the gene. Why it’s awesome is you have extra expression of a gene and you could imagine repressing the levels down to normal. Then of course a therapeutic benefit resulting. Just to expand a little bit about what happens when you have extra PMP 22. This is a protein that’s expressed in the Schwann cells and the Schwann cells are important because they coat those peripheral nerves and they produce myelin. The role of myelin is to provide insulation to support efficient transmission of nerve signals. When you have too much PMP 22 myelination is disruptive and what happens is you get inefficient transmission of nerve signals. So, essentially you can diagnose patients based on the inefficient neurotransmission measured by something called a nerve conduction

Daniel Levine:

Hitting this target is quite different than hitting a target in the eye. Do you have to do something to alter the fatty acids you use, or how do you go about changing one molecule to the next, to hit a specific target?

Arthur Suckow:

There’s a couple of things. In the eye, the fundamental problem is just cellular uptake. You don’t have to worry about leveraging the albumin for distribution. When you come to the systemic applications of the technology where you’ll use intravenous or subcutaneous injections, there’s more optimization because you’re solving for two things, you’re solving for the cellular uptake component of the mechanism, but you also have to be sure that the molecule is around long enough so that it could have sufficient exposure to the peripheral nervous system. So, we explore different combinations of fatty acids, orientations, et cetera, to drive delivery to Schwann cells. I’ll just mention that the approach is not the equivalent of the GalNAc of the Schwann cells. We do get some delivery to other tissues. The idea is that it’s now balanced between these tissues so that you open up a nice therapeutic window versus say a lipid nanoparticle or other technologies that really aggregate in the liver and accumulate preventing your ability to access some of the other tissues

Daniel Levine:

In March you announced a hundred million dollar venture round. What will this allow you to do and how far will it take you?

Arthur Suckow:

The runway is to the end of 2023. The big inflection points for us over the short-term is to continue to generate evidence that this translates to higher species. Across the eye, we just got some exciting NHP data. We’ll move the CMT 1A program to NHP later this year, we’ve got muscle programs going into NHPs concurrent with that. That will enable us to get through those programs and have two to three clinical candidates that are working their way through into IND enabling studies. In both cases, we should be able to dose some of the phase one work.

Speaker 2:

Artie Suckow, co-founder and CEO of DTx pharma. Artie, thanks so much for your time today.

New Speaker:

Thank you, Danny.

 

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