Marrying Antibodies to RNA Therapies to Target Previously Inaccessible Tissues and Cells
January 14, 2022
Antibody oligonucleotide conjugates are a new class of therapies that Avidity Biosciences is developing. These therapies combine the specificity of monoclonal antibodies with the precision of oligonucleotides. The company says by marrying these technologies together it is able to deliver RNA therapies to previously inaccessible tissue and cell types and more effectively target the underlying genetic drivers of diseases. The company is focused initially on muscle diseases but expects to expand out from there. We spoke to Sarah Boyce, CEO of Avidity Biosciences, about its antibody oligonucleotide conjugate platform, how its AOCs can deliver RNA therapies to tissue and cell types that were previously inaccessible, and its lead program in myotonic dystrophy type 1.
Daniel Levine: Sarah. Thanks for joining us.
Sarah Boyce: Thanks so much. It’s a pleasure to join you today.
Daniel Levine: We’re going to talk about Avidity Biosciences, it’s antibody oligonucleotide conjugate platform, and its efforts to develop therapies for rare conditions and including myotonic dystrophy. Let’s start with antibody oligonucleotide conjugates though. People may have heard of antibody drug conjugates, but antibody oligonucleotide conjugates may be a new concept to them. What are antibody oligonucleotide conjugates?
Sarah Boyce: Yeah. To make it easy, we also use the abbreviation AOCs, so it’s a lot like ADCs, antibody drug conjugates, where an antibody is used and a drug is attached to it. What we’re doing is something different. Actually, the antibody oligonucleotide conjugate, or AOC, was invented entirely in house. And what we use as the antibody is like a delivery vehicle to be able to get our drug, which in this case is an oligonucleotide, or think of it as an RNA therapeutic—we’re using the antibody to deliver the RNA to our target cell. Then from there, the RNA can then get into the cell and do its job. So, it’s bringing together two known technologies to be able to do something different. In our case, we’re looking to target different cell types and tissue types than previously were obtainable before.
Daniel Levine: Well, what limitations of oligonucleotides does this allow them to overcome?
Sarah Boyce: Yeah. So, one of the fundamental challenges with oligonucleotides has been that of delivery, and it’s been that of successful delivery outside of the liver. You can deliver oligonucleotides very successfully to the liver. There are many therapeutics that have come out of being able to do that, but delivery to other cells and tissue types has been a fundamental challenge. And that’s where we come in with our technology and we view ourselves as we’re a delivery company, we’re an oligonucleotide delivery company and we’re using the antibody as that delivery mechanism to get our oligo to cells and tissue types that haven’t been achievable before like for example, muscle cells.
Daniel Levine: Do the antibodies simply provide a targeting mechanism or do they provide additional therapeutic benefit?
Sarah Boyce: At the moment we’re just using the antibody as a targeting mechanism.
Daniel Levine: The challenge with antibody drug conjugates has tended to be in the linker. How difficult is it to marry an oligonucleotide to an antibody, get it to release where it’s supposed to in the body?
Sarah Boyce: So, we’ve engineered the technology from scratch so everything matters: the antibody, the linker, the oligo, how you arrange them in space. The linker is important, but as all the other aspects. We’re using a linker that was developed from the ADC world and modifying it somewhat for our purposes, but really every aspect of the technology matter from an engineering perspective.
Daniel Levine: All the nucleotides come in different flavors. Are you able to conjugate any oligonucleotide or are there specific types that work in this way?
Sarah Boyce: Yeah, so one of the other aspects when we were engineering the technology—we did like conjugating different types of oligos—one of the things that’s really driven our choices is where we’ve chosen to use an siRNA approach, so one specific type of oligo, primarily for two reasons. One, they’re very well understood and very well characterized, and you can get this really long duration of action with them. So, we have the potential to dose pretty infrequently, and they’re also very well understood from a safety perspective and have a really good safety profile. So, from there we chose to use siRNAs for our programs when we’re looking to knock down a target. We do have a set of programs in the DMD space, and now we’re looking for exon skipping. So, for there we’re using different type of oligo called a PMO, because we’re looking to achieve a different purpose. So essentially we could conjugate anything we would choose with regards to oligos, but we’ve specifically chosen the siRNAs and the PMOs for DMD.
Daniel Levine: And how do you determine what indications might be best treated with an AOC?
Sarah Boyce: That’s a great question of the aspect of one of the things when you have a technology and you have the potential to deliver it to different cells and tissue types. We started with muscle because in part by the antibody that we identified, and then from there, when we looked at muscle, it was really driven by where is the greatest unmet medical need. If you look at our goal by the end of this year is to have three programs in the clinic for three different rare diseases, all of which there are no approved therapies, our lead program, which is in the clinic today, is in the myotonic dystrophy space. We chose myotonic dystrophy as our lead program, in terms that it made perfect sense as a way to address our technology and from the aspect of there’s no approved therapies available for people who are living with this disease. From a biotech perspective and from an industry perspective of developing drugs for people where we would target the technology first and where there’s people who don’t have an approved therapeutic.
Daniel Levine: At the same time, is there something about neuromuscular conditions that make them particularly attractive to this type of an approach?
Sarah Boyce: I think in terms of one of the elements, we use a transparent antibody. That’s what we conjugate our oligos to and, using a transparent antibody is ideal for targeting muscles. So a lot of it was driven by the receptor that were targeting. There are, though, in the neuromuscular space, there are a set of rare genetic diseases, which have been ideal for an oligo approach. But up until this point, no one’s been able to deliver the oligo. So, from that aspect, there’s lots of work to do, in the neuromuscular space.
Daniel Levine: Well, let’s talk about your lead indication, which as you mentioned, is myotonic dystrophy type 1. For listeners not familiar with myotonic dystrophy, what is it?
Sarah Boyce: It’s a rare genetic disease and it’s caused by a mutation in the DMPK gene where people with myotonic dystrophy have a set of repeats, a set of CG repeats. You and I, we probably have about 30 CG repeats in our DMPK gene; people who are living with this disease can have hundreds to thousands of repeats. What that means is essentially the RNA kind of all gets knotted up and with that a whole load of the splice proteins that are really important for muscle function. So these patients suffer from deterioration of muscle function. They also suffer from where the muscle is unable to release. One of the hallmarks of the disease is someone being able to shake someone’s hand, but not being able to release that grip. Now that sounds pretty simple, but think of it, if you are trying to walk and your calf muscle is contracting, but your calf muscle isn’t releasing, you are going to have some real challenges. It’s a disease that robs people of their independence. It impacts every aspect of their lives. It impacts entire families. and you know, in 70 percent of cases, the primary cause of morbidity and mortality is also cardiac and lung function, because they’re muscles and it impacts those muscles as well.
Daniel Levine: How does the condition generally progress and manifest itself?
Sarah Boyce: Yeah, so it will often progress. Initial manifestations will be that myotonia, but it can be very different from person to person. Sometimes it’s through someone suffering from real GI issues. Sometimes it manifests initially as crippling fatigue. Often what happens is over generations, the length of the repeats get bigger. So, often there’s a child born who is clearly very ill and then the family is tested and we’ve had several occasions where generations are diagnosed within minutes of each other and where you have a grandmother who’s looking after her grandchild because her daughter isn’t well enough to do it. You and the grandmother’s probably going outlive the grandchild. From that aspect, the impact on families is tremendous.
Daniel Levine: It’s one of these conditions where the manifestations of the disease can seem like so many different things. How tough is it to diagnose?
Sarah Boyce: How I think is often the case with rare diseases and particularly where there are no approved therapies. We hear stories of people bouncing from specialists to specialists and taking years to get to a diagnosis because it can present in a whole of different ways. The definitive way is through genetic testing and sometimes that can take a long time for someone to get to the right place, to be able to have that.
Daniel Levine: And how are patients treated today? What’s the prognosis for someone with the condition?
Sarah Boyce: There’s no treatment today, nothing, so it’s really, support to help people with the symptoms of their disease or how it impacts their lives, but that’s it. The research community and the patient community, I mean, they’re incredible, extremely well organized, and actually conducting natural history studies to really get a better understanding of the disease and how it progresses. So, up until we entered the clinic, really for patients, it was to enroll in a natural history study, but that was all that could be done.
Daniel Levine: What is AOC 1001 and how does it work?
Sarah Boyce: Yeah, so AOC 1001 is our first drug to enter into the clinic that’s for the treatment of myotonic dystrophy. How it works quite simply is we’re looking to knock down the DMPK gene and by doing that, we can release what has become clogged up and hopefully be able to make a real impact in patient’s lives by hopefully being able to, at minimum, be able to stop the progression of the disease by allowing the muscles to function better than they can today.
Daniel Levine: What’s known about it from studies today?
Sarah Boyce: It’s pretty well understood from the aspect of natural history. There has been a great deal of work on that and looking at that progression, identifying how to diagnose genetically, and in terms of a treatment approach we do know from a program that went before us, which unfortunately did not progress in the clinic, that if you can knock down DMPK, you can then have an impact on the muscle splicing proteins, which are the things that could impact muscle function. So, kind of like your scientific concepts have been validated.
Daniel Levine: What’s the clinical path forward for you?
Sarah Boyce: Yeah, so right now we have a study called the MARINA study, which is an ongoing phase 1/2 study in patients. and we’re looking to take a midpoint look at that study in the fourth quarter of this year and study completion is October of the following year, and from that, being able to go directly to patients. What that enables us to do is to do is to first and foremost, it’s a phase 1, phase 1/2 study, so your primary objective is around dose selection and understanding safety and tolerability, but we can also learn a lot about the disease as part of that, which will hopefully then inform the design of a pivotal study.
Daniel Levine: I know you’re looking at other neuromuscular conditions, but the technology can be compelling for a range of other diseases. What’s the approach you’re taking to looking beyond these conditions?
Sarah Boyce: We already have programs in the immunology space, also in looking at targeting the heart. We’re doing some of that in partnership. There’s an aspect of almost we have so much potential in what we can do that we’re also working with partners to be able to advance the technology faster than we otherwise could do ourselves. And we’re also already working on how we can advance and improve the technology as well. So, we’ve got a really big agenda. Our goal is to really disrupt the RNA space by opening up all these cells and tissue types that previously no one could target.
Daniel Levine: Do you think of yourself as a platform company?
Sarah Boyce: Yeah, we are. We’re a platform company and we also think of ourselves as a delivery company. We’re looking at how we can best deliver RNA therapeutics to cells and tissue types and that’s enabled through our platform, which is the AOCs.
Daniel Levine: Sarah Boyce, CEO of Avidity Biosciences. Sarah, thanks so much for your time today.
Sarah Boyce: Thanks so much. I really enjoyed our conversation.
This transcript has been edited for clarity and readability.
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