When the term “gene therapy” comes up, the first thing that comes to mind is often some sort of gene replacement or gene editing (either a DNA correction or disruption) to treat a well-defined Mendelian genetic disorder like sickle cell disease or phenylketonuria—not some broad, genetic, complex condition like inflammation or osteoarthritis. Well, unless you are Diem Nguyen, PhD, CEO of Xalud Therapeutics in New York City.

Nguyen is driving the construction of a platform for DNA-based gene therapy that is aimed to help treat pathological inflammation by adjusting the immune system. The company’s most promising product candidate, XT-150, uses interleukin-10 (IL-10), a powerful cytokine that acts as a master regulator for multiple inflammatory pathways, to get to the root cause of inflammation and bring the immune system back to a state of homeostasis. XT-150 is a plasmid DNA gene therapy that can be injected locally. It uses IL-10v, a proprietary version of IL-10, to treat pain and inflammation caused by disease.

The company’s name comes from the blending of the Spanish word for health (“salud”) and the letter “X,” referring to IL-10 as Xalud’s primary target.

Nguyen’s ambitions are backed by 25 years of experience, including significant time spent at Pfizer as global president, Americas, Pfizer Essential Health and Global Sterile Injectables, where she was responsible for commercial businesses in the United States, Latin America, Canada, and Puerto Rico. She was also in charge of commercial development for the sterile injectables business. Nguyen led Pfizer’s efforts to buy Hospira and integrate it to make a leading business with global annual sales of $6 billion.

GEN Edge caught up with Nguyen at last month’s J.P. Morgan Healthcare Conference to hear about her vision for Xalud Therapeutics and the use of non-viral DNA gene therapies for treating complex diseases.

GENE Edge: What’s the science driving Xalud?

Diem: We are actually delivering gene therapy—not for rare diseases but for large chronic indications. We like to say that it’s gene therapy for the masses! We can target such large indications and, ultimately, patients because it’s a non-viral DNA delivery. Everyone is always focused on viral gene therapy, but some challenges are being discovered as it relates to safety.

With the COVID-19 pandemic, suddenly everyone knows about mRNA. What we’ve learned through this process is that there’s a new wave of new therapies that are delivered by gene therapy. The important piece of it is the education on the distinctions between non-viral DNA, non-viral mRNA, and viral gene therapy that most people think about when they think about gene therapy. For us, non-viral DNA delivery is extremely exciting because you can re-dose without worrying about safety because you’re not considering genome integration.

DNA manufacturing is extremely efficient. We’re not talking about significant costs like in AAV manufacturing. We’re not talking about the instability of mRNA that drives more expenses as well as challenges in distribution and storage. Double-stranded DNA is a very stable entity. As a result, the manufacturing efficiency is much higher than with either of the two methods I just described.

I know I’m trying to highlight a lot of the benefits associated with DNA delivery. I’m not saying that one is better than the other. I think everybody has to think about what problem they’re trying to solve and what delivery mechanism will be best to provide a solution.

GEN Edge: Why did you select IL-10 as Xalud’s gene therapy target?

Diem: I like cytokines! If you ask me what to put in a system when you need continuous blocking, our approach wouldn’t be the right disease model. But if you’re looking for just the right enhancement for hormones or cytokines, it’s actually a beautiful way to deliver.

IL-10 is exciting because it’s such a potent cytokine, and this cytokine sits all the way at the top regarding the biological signaling pathways for several inflammatory pathways, like TNF-α and Interferon-γ. Guess which cytokine sits above that? It’s IL-10. So when you think about drug discovery, you’re thinking about targets for inflammation.

Many people have been very focused on some of these downstream targets. Our biology is filled with redundant pathways. If you solve for one pathway, another pathway starts firing—that’s the challenge associated with inflammation. If you stop TNF-α, then suddenly something else compensates for it.

We have the ability to influence multiple pathways because IL-10 sits upstream. The nice thing about IL-10 is that, particularly for osteoarthritis of the knee that we’re working through, it’s not an anesthetic. We’re not blocking pain. We’re not blocking something that’s already firing in your body. What we’re doing is expressing IL-10 and letting it work as an anti-inflammatory by reducing pro-inflammatory mediators. The key is the restoration of this imbalance in your body.

Inflammation is always a balance of anti-inflammatory and pro-inflammatory factors. Pro-inflammatory is good because it alerts you to a problem so you can correct it, but in a healthy body, it is resolved by increased anti-inflammatory mediators, and you live in this normal, healthy stasis state. Interleukin-10 encourages getting back to that balance. I think that’s why we are seeing a long duration of benefit from a therapeutic perspective. Equally important, we are seeing a safety profile that is in a class of its own, when you think about treatments for osteoarthritis in the knee.

GEN Edge: How are you targeting IL-10?

Diem: IL-10 has not been druggable yet, and it’s largely driven by the concept of protein delivery. The protein delivery is adequate, but IL-10s have a short half-life. And you can only do a systemic infusion. So you can only imagine how much IL-10 you’d have to give a patient to show therapeutic benefit with such a short half-life.

Now you solve a bit of that with the fact that you have plasmid DNA that’s endocytosed and continuously expressed in local areas of sites of inflammation. We solved those pieces with the delivery mechanism. The second aspect is that we have a proprietary IL-10 that has shown an extension of benefit in animal models.

We’ve solved two problems here. The first is ensuring you have enough IL-10 that’s not getting eliminated from an activity perspective. Second, this variant has been shown to have a durational benefit.

The transgene and our formulation for delivery to encourage endocytosis of the vector are proprietary, and we have not seen antibody formation associated with our transgene. That’s why it’s so exciting to think about chronic diseases like osteoarthritis and several inflammatory diseases where it’s not a one-and-done. People will suffer from several of these symptoms for the rest of their lives. You want to be able to provide not only a solution but a sustainable solution for patients.

GEN Edge: Where is Xalud placing its chips for the future?

Diem: I have three value creation horizons in mind. Maximizing potential across multiple therapeutic areas is the first step in creating value. IL-10 plays a role in so many disease areas. In some ways, the world is our oyster, especially when it comes to musculoskeletal diseases. So, we’re going after osteoarthritis for the knee and Facet Syndrome for the hip and shoulder. Those are abundant.

The company was founded with the goal of addressing neuropathic pain and the CNS. We’ve published on IL-10 in multiple sclerosis (MS) and its ability to actually slow down the progression in terms of several MS biomarkers, weight, and survival. What’s most exciting to me is that I’m going after ALS. We have shown amazing data on the dose-dependent benefits of neurofilament light chain and other neurogenerative biomarkers. We are looking at astroglial and neuronal health. Most importantly, in our treatment groups of mice, from a survival perspective, it’s astounding.

The therapeutic areas I just outlined are really big therapeutic areas. That could keep any biotech company busy.

But one of my experiences is running large businesses at Pfizer, so I always want more! We’re pursuing a DNA delivery platform. So our thought process here is that we can deliver locally, and we’ve demonstrated that we can deliver across interarticular, intrathecal, and intravital spaces. We’ve also been able to demonstrate reduced inflammation in uveitis as well. I’d like to move on to skin and psoriasis.

One of the areas that we’re looking at is with our vector, where we’re providing chemical linkers that can allow you to attach ligands. That is, it can be administered systemically but with a more targeted tissue targeting approach. By enhancing our platform, I can go after not only IL-10 but many different transgene targets in oncology or any therapeutic area that I think would be amenable to this type of delivery mechanism.

I want to go into another generation of vectors where the promoter senses the environment. For example, with homeostasis, you may see more proinflammatory cytokines coming up, which would trigger a promoter to express the anti-inflammatory gene.

GEN Edge: How is 2023 going to look for Xalud? 

Diem: Xalud is extremely excited about where the industry is moving from a nucleic acid perspective. We are extremely excited about the fact that we’ve been able to solve a drug target that’s so important for many large indications.

I would say that the biotech market needs to continue to fund good science. I understand that there has been some volatility, which has caused people to be hesitant about investing, but I believe that we as an industry need to get back to taking risks and investing in some great scientists because there is still a lot of momentum.

We are such a lucky company to have an abundance of opportunities, but I don’t have the scale or resources to take advantage of all of them. I want to be able to maximize my ability to establish partnerships. Everyone has a certain niche where they would want to be able to consider collaboration. I hope to be able to customize it accordingly.

GEN Edge: How has your experience at Pfizer influenced how you approach Xalud?

Diem: I am so blessed to have been able to work at Pfizer for about 10 years. I’ve had a huge amount of ability to meet some really great talent. With our management team, it’s Pfizer-heavy. Pfizer’s drug development experience lends itself to the uniqueness of Xalud. The leaders I brought in have seen it, been there, and done it. In that regard, we’re really thinking about how we’re building out our drug development programs.

It’s just been such a joy to think about the industry and the willingness of so many great leaders to lean in for a little biotech tech company. I’m very proud of our organization and how efficient and thoughtful we are in terms of our efforts to bring medicines to patients.

The post To Health: Xalud Therapeutics Is Bringing Gene Therapy to the Masses appeared first on GEN - Genetic Engineering and Biotechnology News.

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