Targeting The Uncharted Heart: Why The Next Era Of siRNA Belongs In Cardiology
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Why RNA?
It seems like a simple enough question, but the answer(s) can be quite nuanced. On the one hand, our entire industry is working to answer this question iteratively as we enter and move through the clinic with our RNA candidates. We ultimately need to understand what RNA medicines bring clinically to the table that other available modalities might not — answers that we’re certainly starting to get in the oligo (siRNA/ASO) sectors. But in my conversation with Kath Gallagher, the CEO of the newly launched Atrium Therapeutics, we also delved into why it is the right time to be entering the RNA development space.
As Gallagher and I discussed in part one of this two-part series, there has been a lot of buzz around the RNA space this past year, with Novartis’ $12 billion-dollar acquisition of Avidity’s AOC platform and the subsequent spin-out of Atrium being just two prime examples. But exploring next-gen RNA delivery strategies is just one reason it is such an exciting time to be working within the RNA space.
“What excites me most is that the RNA space — particularly the siRNA sector — is an open field,” Gallagher said. “Most RNA development to this point has been focused on the liver. Now, there is a whole pack of companies going after the neuromuscular space following successes delivering to the skeletal muscle.” But as she went on to explain, there are still so many areas ripe for therapeutic investigation, including in the cardiology space. Enter Atrium, with its eyes trained on treating rare genetic cardiomyopathies.
As I prefaced in part one, entering the rare disease space is not for the meek. It requires forging a path into and through an unscripted regulatory environment, as well as forming incredibly close relationships with the patient community. During our conversation, Gallagher walked me through what’s keeping her up at night as she leads the company and its first siRNA candidate toward an IND, elaborating on the role RNA can play in cardiomyopathies and identifying the unique challenges of developing RNA medicines today.
The Role of RNA Medicines In Cardiology
The heart is a vastly misunderstood organ.
This could be the beginning of a love poem. But for Gallagher, it’s also a scientific truth. While there has been a lot of investment and research into liver-based and neuromuscular conditions throughout the past few decades, the cardiology space is much further behind. Not only is reaching the heart challenging from a therapeutic delivery perspective, but we often adopt a siloed way of looking at the heart and the ways in which it can be injured. As Gallagher went on to explain, many people don’t think of the heart as a muscle. Most people tend to think predominantly of cardiovascular disease.
“We’re not going after cardiovascular disease; we are going after diseases where the heart muscle is not working the way it needs to work,” she clarified. “We’re in this incredible time in the cardiology space right now where so few people are being genetically tested. As such, most people with cardiomyopathies are treated symptomatically for heart failure, but the medicines prescribed don’t treat the underlying cause of the disease. In many cases, we don’t even know the underlying cause of disease.”
There are several reasons why working on RNA therapeutics for cardiomyopathies excites Gallagher. On the one hand, RNA has proven that it’s capable of exerting the necessary “knock-down” action when delivered to the desired tissue. Likewise, seeing as Atrium is a descendent of Avidity, which has experience working in skeletal muscle, it made a lot of sense to continue to focus on another type of muscle. In fact, during Avidity’s preclinical studies on NHPs for rare neuromuscular disease, the company observed delivery to the heart, as well as to the skeletal muscle.
Of course, there remains a lot to learn and understand about delivery to the heart and the specific targets. While Atrium has chosen to use an antibody to target the transferrin receptor to get the drug product to the heart, reaching the specific cardiac muscles remains an uncharted course. Not to mention there remain unknowns about whether there are other important targets in PRKAG2 syndrome (the company’s lead indication) that are influential in causing the disease.
“When I think about potential challenges we’ll face, it isn’t so much the modality itself; it’s the unknowns around the underlying root causes of cardiomyopathies,” she explained. “There’s been a lot of research demonstrating that the PRKAG2 gene is the cause of PRKAG2 syndrome. But we won’t know for certain until we test in humans.”
Regardless of the intimidating biological uncertainties inherent in any drug development program, Gallagher reiterated her belief in the RNA modality as a potential answer for patients suffering from cardiomyopathies. Though we may be representing chronic therapies in this era of “One-and-Done,” we’ve also witnessed what were once fatal diseases now become manageable and treatable diseases, thanks to RNA. The data on siRNA products’ safety and efficacy is already strong and continues to grow. However, as Gallagher underscored, RNA may not necessarily be the answer for every person. Having a variety of different modalities to choose from — including RNA — should be the end goal.
“I’m a big believer in the fact that more research in these spaces helps patients — whether it results in an RNA therapeutic or not. Choice is good for patients.”
Unpacking Pharma’s Responsibility to Patients & Physicians
In the RNA space, broadly speaking, we often emphasize the importance of educating the general population about RNA medicines. It goes without saying that understanding the mechanisms behind how RNA medicines work, as well as their safety and efficacy is essential, whether it be to fight misinformation or simply articulate the benefits of RNA so patients know their choices.
However, educating physicians is just as important — if not more important — than educating the public today. After all, when it comes to treatment choice, patients listen to and trust their doctors first and foremost.
As Gallagher pointed out, physicians — particularly in cardiology — know little about RNA therapeutics today. Though the knowledge of RNA is a bit more engrained in the neuromuscular space thanks to concerted efforts to broaden the treatment landscape, the cardiology field remains much more nascent. As Gallagher pointed out, there is some knowledge of RNA in the transthyretin amyloid cardiomyopathy (ATTR CM), thanks to Alnylam’s Amvuttra. But there is clearly a lot more room to grow.
“RNA has been around for such a long time, but only in certain smaller indications,” Gallagher said. “So, as we start going into much broader indications, the education also needs to scale so physicians understand what an siRNA is and how it works, as well as how it’s different from an mRNA.” As she went on to explain, the fact that Atrium’s first product is also an AOC adds the additional complexity of explaining the ‘why’ behind the antibody and how it’s not for therapeutic effect.
Fortunately for us, Gallagher is incredibly optimistic that our efforts to educate will be met favorably by the medical community, especially considering the next generation of cardiologists are learning much more about genetic disease today. Not only does this make them more informed about the underlying genetic causes of disease, but this also means genetic testing can become more commonplace, leading to earlier, more informed discussions about how to treat the root cause of a disease.
Much of my conversation with Gallagher centered around responsibility — namely how much can and should be carried out by individual companies as opposed to the whole industry. As she nicely articulated, companies that are first to an indication have a responsibility to “Pave a path in a way that opens a lot of doors and choices for patients.” For Atrium, this means a couple different things — the most important being designing clinical studies and getting a product into the clinic this year to demonstrate to investors, patient groups, and physicians that the company is doing what it said it would do. Of course, this also means establishing water-tight relationships with patient advocacy groups to ensure that clinical trial design is informed by patient and physician input. As she went on to emphasize, a large part of Atrium’s first year on the market will be dedicated to listening.
“We have to design the right studies to ensure the answers we get push the field forward. That’s part of our responsibility,” she said.
However, when it comes to stakeholder education, we will be much stronger outside of our individual stakeholder silos (i.e., biotechs, scientific organizations, patient advocacy groups).
“A fifty-person company will be much stronger by partnering with patient advocacy and scientific organizations on educational initiatives,” Gallagher concluded. “Together, we need to
identify in which areas we can shed more light. For example, how do we encourage more people to get genetic testing? How do we get genetic testing to be more of a standard of care than it is today? What efficiencies can we build into development programs that will not only be the fastest but also the most beneficial for patients?”
Miss part 1? Check it out here: Following the Data to the Heart: Atrium's Quest for Next-Gen Targeted RNA Delivery