Nonviral Gene Therapy Harnesses IL-10, Tames Inflammation

A locally injectable plasmid DNA formulation from Xalud Therapeutics can downregulate pro-inflammatory cytokines through expression of an IL-10 variant

Chronic inflammation is a hallmark of multiple conditions in the musculoskeletal and neurodegenerative spaces. Although many companies are addressing inflammation, delivery has been complicated in terms of safety and efficacy.

Xalud Therapeutics is developing a fundamentally different approach, shaking up the sector. It is using a nonviral, DNA plasmid delivery platform to induce the expression of an IL-10 variant that can modulate a number of downstream pathways, suppressing pro-inflammatory cytokines and resolving inflammation.

“We are going after large, chronic diseases to provide a medication that is safe, efficient, and effective for millions of patients,” says Diem Nguyen, PhD, Xalud’s CEO. The company’s lead program targets osteoarthritis of the knee.

Potential for redosing

According to Nguyen, using a nonviral DNA delivery platform allows the company to “avoid some of the challenges that are associated with viral delivery mechanisms.” One of these challenges is immunogenicity. It prevents viral gene therapy from being administered more than once even though a single administration may be insufficient to resolve chronic conditions. Immunogenicity is less of an issue with Xalud’s gene therapy approach. Xalud’s approach, Nguyen emphasizes, is advantageous because it allows repeat injections over time.

This ambitious company applies a novel approach that may enable a fundamentally different, effective way to treat inflammation and associated symptoms, as well as a potentially better way to deliver gene therapies. Xalud is one of the few companies in the DNA delivery space that can boast of having drug candidates in late-stage clinical development.

Potent immune modulation

Xalud’s lead compound, XT-150, is a DNA plasmid that expresses a proprietary modified variant of IL-10 directly at the injection site.

IL-10 is a potent, upstream immune modulator of inflammation. It can modulate multiple pathways by suppressing the expression of various cytokines. “We’re downregulating multiple pro-inflammatory cytokines that resolve inflammation through the expression of our IL-10 variant,” Nguyen notes.

“Drug developers have known the importance of IL-10 for decades,” she continues, “but this cytokine [poses difficulties]. IL-10 is found throughout the body and has a half-life of about two to four hours.” Infusions would have to deliver a large enough quantity of IL-10 to initiate and sustain the attenuation of inflammation.

Xalud’s approach avoids the difficulties of IL-10 infusions. The company deploys plasmid DNA that induces expression of a long-acting IL-10 variant. Direct injection of the plasmid DNA at the inflammation point minimizes systemic exposure and ensures that the drug is delivered exactly where it is needed most.

Once the plasmid DNA is injected, it is engulfed by the cells of the local tissue as well as by macrophages. Then the plasmid DNA drives the expression of the IL-10 variant at the site, resolving inflammation by restoring homeostasis.

Clinical trials for multiple indications

Currently, Xalud has three programs in clinical trials—one is for osteoarthritis of the knee (Phase IIb), one is for neuropathic pain (Phase I/II), and one is for facet joint syndrome (Phase I/II). The safety profile has been strong to date with no serious adverse events associated with the drug. No antibodies have been generated against the plasmid or the protein of interest.

The second round of clinical development may include neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). “We have tantalizing preclinical data for ALS and uveitis,” Nguyen remarks. “And we are looking at a number of other chronic inflammatory disease areas, including dermatology.”

She also mentions that the company has plans to build out a DNA library of candidates, and that it is looking at additional transgenes that are suitable for its DNA delivery platform across multiple therapeutic areas.

Novel mechanism of action

“We don’t want to block the inflammatory response, like a lot of non-steroidal anti-inflammatory drugs (NSAIDs), or to mask the pain symptoms associated with inflammation, like steroids,” Nguyen says. “Instead, we’re trying to help stimulate a resolution of the inflammatory pathway to bring your body back to homeostasis.

“After an injury or an immune activation occurs, a healthy body will upregulate a number of pro-inflammatory cytokines, telling the body that it is hurt. Then the body will react by increasing the expression of anti-inflammatory mediators. At Xalud, we are trying to encourage the body to reduce the pro-inflammatory cytokines and thereby stimulate this resolution pathway.”

Once the inflammatory response is activated, it reaches a peak phase and then proceeds to resolution—unless it veers into chronicity, raising the risk of inflammatory disease. To promote resolution, Xalud Therapeutics is developing XT-150, a locally injectable plasmid DNA gene therapy for expressing a modified interleukin-10 variant. XT-150 has been optimized for characteristics such as dosing and formulation, and it modulates inflammation through multiple pathways. It is being evaluated for multiple indications, including osteoarthritis of the knee. [Adapted from Schett and Neurath, Nat. Commun. 2018; 2018; 9(1): 3261.]

If resolution of the inflammatory pathway is to be stimulated, Xalud must overcome several challenges. The first challenge is to demonstrate that the approach is safe and tolerable and has no unintended consequences. “We have dosed more than 300 patients with single or repeat injections, and we have found it to have a very safe profile,” Nguyen asserts.

The second challenge is to demonstrate efficacy. Currently, Xalud is confronting this challenge with its lead indication, osteoarthritis of the knee. “Running trials in this space is very difficult because of the subjective nature of the endpoints,” Nguyen observes, “[We need to design] a trial that addresses meaningful, holistic patient benefits in a real-world setting. With a large unmet need and growing addiction to opioids, we need to ensure that we are providing solutions that are safe for patients.”

The third challenge is to show that patient benefits are durable. To that end, clinical trials are examining the concept of single and repeat injections. Participants are exhibiting prolonged benefits and sometimes an enhanced benefit associated with a subsequent injection.

A magnet for investment and talent

The company was spun out of the University of Colorado in 2009. In 2015, it found a major investor in PBM Capital. “It was enamored with the potential it saw in many of the preclinical studies—particularly in dogs—for improved motility as well as function,” Nguyen relates. “Then, during the next five years, there was significant investment to move into clinical programs.”

Nguyen joined the company as CEO about a year and a half ago. She came from PPD, where she was executive vice president of biopharma. Previously, she held a senior position at Pfizer, in a division focused on sterile injectables.

To explain the transition to Xalud, Nguyen highlights three points. “The first thing that struck me was that Xalud was addressing such a large unmet need. It wasn’t looking for a ‘me too’ product, but at a fundamentally different way of treating a certain indication.

“The second thing that attracted me was that Xalud was at an inflection point. The number of areas we can pursue is quite extensive.

“The third thing is that I got to build an amazing team.” Team building, Nguyen acknowledges, is especially challenging when so many people have become accustomed to meeting online. Nonetheless, she is committed to sustaining creativity and brainstorming activity among Xalud team members who contribute expertise in immunology, neuroimmunology, and clinical development.