Transforming the Treatment of Neuromuscular Diseases with Next-Gen Oligonucleotides

Oligonucleotide therapies can target the root cause of many diseases through the modulation of RNA expression and processing. Despite the promise of these medicines, their development has been limited by delivery challenges because they are not able to adequately reach heart and skeletal muscle, the critical affected tissues in neuromuscular diseases. PepGen is advancing next-generation oligonucleotide therapeutics that leverage its delivery platform technology to produce cell-penetrating peptide conjugates that improve the activity and tolerability of oligonucleotide therapies. We spoke to James McArthur, president and CEO of PepGen, about the company’s platform technology for conjugating peptides with oligonucleotides, how this allows it to target hard to reach tissue, and why it opens the potential for new therapies to treat neuromuscular and other diseases.

Daniel Levine: James, thanks for joining us.

James McArthur: Thank you very much, Danny.

Daniel Levine: We’re going to talk about PepGen, its enhanced delivery oligonucleotide platform, and its pipeline of therapies in development. Let’s start with oligonucleotides. This is a promising area of emerging therapies, particularly in the realm of rare genetic diseases. What makes oligonucleotides so compelling?

James McArthur: It’s a modality that has been around for quite some period of time and really in the last several years has shown promise across a variety of therapeutic areas. In spinal muscular atrophy and a variety of other rare genetic diseases, different types of oligonucleotide therapies have shown the ability to fundamentally alter the course of diseases of patients with rare genetic diseases. In the area of neuromuscular diseases, there are several approved drugs, particularly for the treatment of Duchenne muscular dystrophy that have also shown promise, but many people think could still be made much better. And that’s why we’re focused on this space.

Daniel Levine: How do these therapies work?

James McArthur: So, different types of oligonucleotides have different effects. The type that we’re using, PMOs, are a stable artificial RNA that has the ability to essentially interact with other RNAs and block either their interaction with proteins or block their interaction with specific sites and in doing so we can actually change their properties and change their behaviors.

Daniel Levine: What would make a disease a particularly good candidate for this type of approach?

James McArthur: Well, the starting point is a clear understanding of the underlying genetic etiology or cause of the disease. And then for our particular approach, understanding that introducing one of these stable molecular species that can go and block a particular interaction would alter that or change that outcome. And so that’s what we’re really focused on. The nice thing is we know if we’re successful in delivering our PMOs, our therapeutic oligonucleotides, into the muscle cells that really matter that we can really fundamentally change the course of the disease.

Daniel Levine: Oligonucleotides have already demonstrated their utility, but there are challenges around the ability to target different tissues and cell types within the body. How much of a problem does this represent? How has it limited our ability to realize the full potentials of these therapies?

James McArthur: Yeah, so people have begun to address this in a couple of different ways. One, introducing it directly into the tissue you’re going after. So, if you’re going after SMA, you can introduce it directly into the spine where the cells that are impacted live and essentially get the oligonucleotide to the cells that matter. In the case of ocular diseases, people have done the same, introduced them directly into the eyeball. Or you can target them following intravenous administration and targeting so far has been mostly focused on targeting to the liver where a variety of treatments have been approved for different rare genetic diseases. For neuromuscular diseases, this is an area where we’re now just beginning to really expand the potential of our ability to go and deliver therapeutic oligonucleotides to the muscle cells, where we need to get these oligos to go and impact things like the Duchenne muscular dystrophy or myoonic dystrophy.

Daniel Levine: PepGen has what it calls its enhanced delivery oligonucleotide, or EDO platform. What does this platform do and how does it work?

James McArthur: We’re fortunate that we were working with two academic collaborators in the U.K. who had spent a decade essentially identifying what they believed would be the optimal sequences to go and deliver all the oligonucleotides into muscle cells. And so we took a series of these molecules forward and identified one in particular. That’s the basis of our EDO technology that has the ability to deliver with extremely good efficiency in preclinical models, mice and non-human primates, therapeutic oligonucleotides to muscle cells and also get meaningful levels delivered to the CNS as well. And we’re now essentially taking these molecules and translating them clinically with a phase 1 clinical study to see, indeed, can we reproduce the data that we have in non-human primates in humans?

Daniel Levine: My understanding is part of the way your platform works is that you’re linking the oligo to a peptide. How challenging is it to link those two?

James McArthur: So, the particular peptides that we’re using are relatively short peptides, fewer than 20 amino acids. So, that doesn’t present a significant constraint compared to say much larger protein species and we can in a directed fashion using both innovative, but also quite simple chemistry, directly attach the oligonucleotide to this peptide so they remain attached together. We deliver them as a single drug when we deliver them by IV intravascular administration. And they then allow the delivery of the oligonucleotide to the muscle cell.

Daniel Levine: Is the peptide serving as a targeting mechanism?

James McArthur: Our particular approach does not appear to be focused on a specific receptor, but instead allows increased uptake into the muscle cells and other cells like cells in the CNS. So, the process, which we are still trying to figure out the exact mechanism, appears to be both the association with the cell membrane and then allowing the very efficient transfer across the cell membrane of both the peptide as well as the oligonucleotide.

Daniel Levine: And is it understood what happens to release the oligo at the desired site?

James McArthur: We don’t know at this point exactly the mechanism by which it’s released, what we do know is that we get more oligo into cells with this approach than with other technologies that have been described. And we also know that we’re able to get the oligonucleotide into the nucleus, the center of the cell, where it needs to be to go and mediate the action whether it be in DMD or myotonic dystrophy.

Daniel Levine: My sense is that oligonucleotides can have a rather short half-life. Is there any challenge in getting the oligo to remain intact until it’s delivered?

James McArthur: So, it’s relatively short in terms of the half-life floating around in the blood, but it’s actually quite long in the cells themselves. So once we get it into the cell, PMOs are a very stable molecular species and actually are believed to be able to stick around for several days.

Daniel Levine: You’ve got two lead programs. You had referenced Duchenne muscular dystrophy earlier. You’ve also got a program in myotic dystrophy type 1. For listeners not familiar with Duchenne, what is it, and how does it manifest itself and progress?

James McArthur: Sure. Duchenne muscular dystrophy is a particular muscle disorder where a very large protein called dystrophin—it’s actually the largest protein in the body that essentially connects the intracellular architecture with the extracellular architecture through the membrane. And this protein both acts as a connection between the intracellular machinery and the cell membrane, but also acts as a shock absorber in muscle cells, allowing them to contract and expand and contract and expand without literally tearing the cell to pieces. In the absence of this protein, which is what happens in Duchenne muscular dystrophy, where due to either stop codons, you know, where essentially you make an incomplete protein, or where you make a protein that has other deficits, either is missing big chunks or in other fashion is deficient—that protein is not there to go and do this function. And essentially over time, the muscle cells destroy themselves. Now, what we’re trying to do is create a slightly shortened version of the native dystrophin protein, but one that still captures all of its normal functionality both from connecting the architecture and acting as a shock absorber within the cell.

Daniel Levine: What therapeutic options exist today and what’s the prognosis for patients with the condition?

James McArthur: The prognosis for patients has improved over the years with the introduction of different steroids and steroid regimens. We can cut down on the inflammation and slow the progression of the disease. And now there are several approved drugs for specific types of Duchenne muscular dystrophy that have been approved. We’re essentially using the same sort of approach. They produce a slightly shortened dystrophin protein. And although the levels of dystrophin protein that these approaches produce are quite low, they do seem to have some ability to ameliorate the disease. I think patients, though, are waiting for that next generation of therapies, therapies that take them to the next level in terms of much higher levels of dystrophin production that will allow better lives, fuller lives both from the standpoint of functionality, as well as life expectancy.

Daniel Levine: Your lead therapeutic candidate is for patients who are amenable to exon 51 skipping, Perhaps you can explain what exon 51 skipping means.

James McArthur: Sure. So, exons are portions of the RNA that end up being translated ultimately into protein. So they’re part of the normal mature RNA that end up getting turned into protein. They essentially are the architectural blueprints from which we make the proteins like dystrophin. Now in the case of exon 51 it’s as if you’re missing a big chunk of that architectural blueprint, and can’t figure out how to finish the house, if you will. What we’re doing is providing essentially an outline of what that area would look like, allowing us to finish the house. So we’re missing a particular region, exon 51, but we still have most of the other regions present in this slightly shortened protein. And in that fashion, we can go and complete the house.

Daniel Levine: This may sound familiar to listeners because Sarepta won approval for an exon 51 skipping oligonucleotide for Duchenne. Why start there as this would put you in direct competition with an existing therapy.

James McArthur: That’s a great question. So, you’re absolutely correct. There is an approved therapy for exon 51 skipping called Exondys 51, and as I’d mentioned, it produces quite low levels of dystrophin protein. What we’re trying to do here is follow, if you will, the same regulatory path that has been laid out, and hopefully this will allow us to more rapidly translate from exciting research in the laboratory to a therapy that ultimately really has a profound impact on the outcome of this disease in patients with Duchenne who are amenable to this a particular approach. We believe that we can produce much higher levels of this slightly shortened dystrophin protein, and that has the real potential to benefit patients. And so we are benefiting from all the tremendous work that’s gone on before us to lay out a path to getting out a drug approved. We know what we need to achieve, and we’re seeking to go and achieve that with our EDO51 molecule.

Daniel Levine: What’s the development path forward. And given what you just said, does that suggest there’s some accelerated pathway to get there?

James McArthur: Yeah, so we’re right now in a phase 1 healthy volunteer clinical study. So these are individuals who volunteer for the clinical study, who do not have the Duchenne muscular dystrophy. Now, the reason we begin there is that we believe that this offers an accelerated path to translate from really exciting preclinical data in mouse and non-human primates to patients. It allows us to rapidly figure out what is the right dose, what is the dose that’s safe, and what is the dose that we get meaningful levels of oligonucleotide into muscle that will produce meaningful levels of exon skipping ultimately in patients. So we can conduct this study in less than a year, whereas a patient clinical study will take us a year and a half to two years to get the same sort of answers. So we think ultimately we can accelerate the development of this therapy by pursuing this particular path. Ultimately, we’ll need to be able to demonstrate that indeed we are producing meaningful levels of this slightly shortened dystrophin protein in patients, and then would seek accelerated approval as other drugs targeting different exon skipping approaches have done before us.

Daniel Levine: I mentioned you’re also working on developing a treatment for myotonic dystrophy type 1. How does that condition manifest itself and progress?

James McArthur: Sure. Before I go there, I want to also highlight that we are also looking at other exon skippable patient populations. So, exon 51 is the largest of these patient populations, but we also have programs in research and preclinical development for exon 53 and 45 and 44. Our hope is to be able to translate our work in with exon 51 into all of these other and then beyond to be able to treat a larger and larger portion of the DMD patient community. Now, myotonic dystrophy is quite a different disease. In this particular disease, you produce an RNA that has an elongation of a region that normally exists, but in producing this elongation, what’s called a triplet repeat, you produce a molecular structure in the RNA that looks like a hairpin loop, essentially a great big looping out of the RNA. Now this big looping out of the RNA acts essentially as a sponge for many proteins that typically bind to these sorts of structures, including a protein called muscleblind 1. Now this protein is a protein that has many effects inside the cell and when it gets attached to the sponge, it ultimately can’t do its normal function. And a whole bunch of different RNAs are essentially inappropriately produced. Now, what we’re trying to do here is stop muscleblind 1 binding to the sponge in a very safe and effective fashion. And in doing so allowing muscle blind 1 to do its normal function. Now in most studies, we can see that at a molecular level we can accomplish this using our EDO-DM1 drug. And we can also demonstrate in mice, where they have myotonia, this propensity to go and freeze when they’re touched, where they cannot move their muscles anymore that we can essentially prevent this with our EDO DM1 technology. And so we have been advancing this program forward, doing all the necessary studies before entering clinical studies, which we hope to begin in patients who have myotonic dystrophy type 1 in the first half of next year.

Daniel Levine: What treatment options exist today for DM1 and what’s the prognosis for patients?

James McArthur: Right now, only palliative care is available to these individuals and essentially, they suffer from both a freezing of the muscles, muscle weakness across a variety of different tissues, including the limbs as well as the heart. But they also suffer from neurologic components, everything from anxiety, confusion, and a variety of other neurologic manifestations because essentially muscle blind protein has this impact in so many different tissues in the body. And here’s where we’re really hoping the EDO technology can be very helpful because, as I’d mentioned early on, we not only see improved delivery to muscle cells, we can also see improved delivery to the CNS, to the brain. And so we might be able to impact some of the neurologic manifestations of the disease in addition to the muscular manifestations of the disease.

Daniel Levine: PepGen completed an IPO in May in what’s been an unwelcoming market for biotech issues, to say the least. You did go below your expected range and needed to increase the size of your offering. Why the decision to go public now?

James McArthur: We raised this capital on the back of a significant funding round we did last year to go and fund the company through pivotal data readouts in patients in 2024 and beyond. So, in 2024, we anticipate that in DMD patients amenable to an exon 51 skipping approach, we will be able to demonstrate with the EDO 51 program the production of meaningful levels of dystrophin protein in patients. Also in 2024, we anticipate, in myotonic dystrophy type 1 patients, being able to demonstrate an impact on the molecular underpinnings of this disease and show the correction of those molecular underpinnings, be able to show the correction of splicing, showing that we indeed have liberated muscleblind 1 protein. We have raised now enough capital to both expand the team to go and accomplish these as well as take the company well beyond these points. So we are capitalized into at least the first half of 2025.

Daniel Levine: There’s still a fair bit of private capital available today. Why the decision to go public?

James McArthur: We decided there were some advantages of doing this for us including broadening our investor base, as well as being able to realize the potential of additional financings in the future, in the public market case, in the case that it actually makes sense both from a standpoint of where the markets are as well of as how the data is evolving.

Daniel Levine: James MacArthur, president and CEO of PepGen. James, thanks so much for your time today,

James McArthur: Danny. Great chatting with you.

This transcript has been edited for clarity and readability.