Solving the IL-10 Delivery Problem

Xalud Therapeutics is developing a novel plasmid (pDNA) gene therapy delivery platform that has emerged as part of a new and exciting wave in the nucleic acid therapeutic space. The platform provides an elegant solution for a longstanding struggle to harness the power of interleukin 10 (IL-10)—a potent anti-inflammatory cytokine that serves as a master regulator to suppress key pro-inflammatory cytokines. XT-150, Xalud’s lead candidate, expresses an enhanced proprietary version of IL-10 which has been developed to overcome historical delivery challenges—potentially reimagining the treatment of many diseases caused by chronic inflammation affecting hundreds of millions of people worldwide.

The Role of IL-10 in Chronic Inflammation

Cytokines, from the Greek cyto (cell) + kinesis (movement), are what cells use to talk to each other—a kind of “cellular text messaging.” Cytokines play a critical role in driving the inflammatory response—or quelling it. Under normal, healthy conditions, the cytokines are in a state of homeostasis—with a balance of pro-inflammatory and anti-inflammatory cytokines. In response to an injury, the acute pro-inflammatory response lasts for a brief period after the injury, and afterwards, homeostasis is restored by anti-inflammatory cytokines. Chronic inflammatory diseases occur when the immune system is unable to return the body back to this balance of cytokines. The result is a continuous cycle of immune dysregulation, including a cascade of uncontrolled cytokines and inflammatory cells that pushes the body further from its balanced state. Over time, chronic inflammation leads to damaged cells, tissue death and further disease progression. In order to treat inflammatory diseases in an effective, safe, long-lasting and disease-modifying manner, patients require a therapeutic approach addressing the master regulator that can reduce inflammation through multiple pathways.

Enter IL-10, a known master regulator and modulator of the immune response. Studies have shown that natural activation of IL-10 is effective in counteracting the inflammatory response across a broad range of diseases, thereby preventing or mitigating damage that occurs when homeostasis is disrupted. ?In addition, there is evidence that in diseases such as osteoarthritis (OA), low levels of IL-10 production by blood cells are correlated with greater disease symptoms. This inflammatory cascade has also been shown to play a role in the brain and in neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Pro-inflammatory cytokines have been observed in MS patients along with IL-10, which is thought to represent the body’s mechanism to preserve neuronal integrity through its anti-inflammatory effect.

XT-150 Overcomes Historical Challenges

Knowing that IL-10 is an important player in fighting chronic inflammation, several efforts have been made over the years to harness its full potential to develop a therapeutic that would be safe, effective and easily delivered. Previously, IL-10 has eluded drug development because, as a systemically delivered protein, it is rapidly cleared and attains low target concentrations. IL-10’s half-life is around two to four hours and has previously required too many repeat doses to be used in the clinical setting. ?

Xalud’s lead candidate XT-150, a new treatment opportunity for chronic inflammation, is a naked plasmid designed to transiently express an enhanced IL-10. Xalud’s proprietary version of IL-10 has shown longer duration of effect compared to wild-type IL-10.?In addition, because this is a non-viral approach with naked pDNA, there is no host integration (resulting in a favorable safety profile), no antibody formation (which allows for repeat dosing without waning effects) and efficient, cost-effective manufacturing.

XT-150 can be injected directly into the inflamed area, such as the knee joint, to enable the expression of IL-10 where the body needs it the most. The injection of the plasmid supplements the body’s own IL-10 activity to better counteract its pro-inflammatory state and restore immune system homeostasis. Overall, XT-150 represents a potentially transformative solution that provides significant improvements in expression, duration and efficacy—which we believe will provide a solution to the IL-10 delivery dilemma.?

Reimagining the Treatment of Chronic Inflammation

In the chronic inflammatory disease space, many patients have exhausted treatment options and continue to seek safe, long-term relief. Some options are too potent, and when systemically delivered, lead to serious adverse events and widespread toxicity. Others simply mask disease symptoms rather than addressing the root source of pain and inflammation. A great example of this is OA of the knee, where one study indicated that up to 70 percent of patients may have developed an inadequate response to conventional analgesics.

Xalud’s lead program is for OA of the knee with Phase 3 studies being planned for 2023. Clinical studies conducted to date for the treatment of knee OA with XT-150 show a highly favorable safety profile and clinically meaningful, long-lasting improvements in pain, function and knee performance. Xalud is also conducting ongoing clinical studies in indications such as facet joint syndrome in addition to preclinical work in neurodegenerative diseases such as ALS and MS.

As Xalud continues to advance programs in several chronic inflammatory indications, we are also exploring how our platform may have potential for other DNA-delivered therapeutics and enhanced delivery. This is an exciting time for the Xalud team, and we look forward to working closely with patients, principal investigators and regulators to bring our novel therapeutics to the millions of patients that need them.